Multiparametric Whole-Body Anatomic, Functional, and Metabolic Imaging Characteristics of Peripheral Lesions in Patients With Schwannomatosis

Abstract

Purpose:

To describe the anatomic, functional, and metabolic characteristics of peripheral nerve sheath tumors (PNSTs) in patients with schwannomatosis (SWN) on whole-body magnetic resonance imaging (WB-MRI) (anatomic and functional imaging) and fluorine-18-fluorodeoxyglucose positron emission tomography / computed tomography (FDG-PET/CT) (metabolic imaging).

Materials and Methods:

WB-MRIs at 1.5T and 3.0T performed in 13 SWN subjects using short tau inversion recovery (STIR), T₁-weighted (T₁W), contrast-enhanced T₁W, and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping and FDG-PET/CT were retrospectively reviewed. Two readers reviewed all imaging for the presence and character of peripheral lesions (size, imaging features, ADC values, and standardized uptake values [SUV_max]) and ancillary findings. Descriptive statistics are reported.

Results:

In all, 153 index lesions were characterized in 13 patients on WB-MRI. Lesions were characterized as tumors (97% [149/153]) or cysts (3% [4/153]); 96% (143/149) PNSTs were solitary while 4% (6/149) were plexiform. The median size was 2.3 cm (range 1–24.3 cm). On T₁W, 99% (148/149) tumors were homogeneously isointense; on STIR, 81% (121/149) tumors were heterogeneously hyperintense; on postcontrast T₁W, 81% (100/123) tumors enhanced heterogeneously; on DWI, tumor ADC values (×10⁻³mm²/s) were variable (minimum ADC range 0.3–2.2, average ADC range 0.9–2.9). The median SUV_max was 6 (range 2.1–11.7) and 10 (2.7–15.3) on early and delayed imaging, respectively. Malignant degeneration was detected in 1% (1/149) with suspicious anatomic, functional, and metabolic characteristics. Ancillary findings included nerve root thickening (23% [3/13]) and spinal canal lesions (15% [2/13]).

Conclusion:

Although the majority of the PNSTs in SWN are benign and solitary, PNSTs can be plexiform, enlarge over time, and, rarely, undergo malignant degeneration. Due to the high metabolic activity in benign PNSTs by FDG-PET/CT in SWN, WB-MRI with functional sequences maybe a more suitable technique for the assessment of disease burden, tumor characterization, and surveillance.

The neurofibromatoses (NF), comprised of neurofibromatosis type 1 and 2 (NF1 and NF2) and schwannomatosis (SWN), are a diverse group of inherited syndromes with a predisposition to the development of multiple peripheral nerve sheath tumors (PNSTs). Schwannomatosis, a rare disorder of unknown prevalence and similar incidence to NF2, is a recently recognized NF syndrome characterized by the development of peripheral schwannomas, reportedly in the absence of bilateral vestibular schwannomas, which are diagnostic of NF2.^1–8 Schwannomatosis can manifest as a localized process due to mosaicism or present with multifocal PNSTs. The majority of cases of SWN are sporadic, with inherited cases constituting a small proportion of patients.^2–6 Only 10% of sporadic and 50% of inherited cases have a known identifiable genetic mutation.^5,6 Hence, the diagnosis of SWN hinges on clinical criteria in addition to genetic testing (Table 1).

TABLE 1.

Diagnostic Criteria for Schwannomatosis ¹

Molecular diagnosis:

2 or more pathologically proved schwannomas or meningiomas AND genetic studies of at least two tumors with loss of heterozygosity (LOH) for chromosome 22 and two different NF2 mutations; if there is a common SMARCB1 mutation, this defines SMARCB1-associated schwannomatosis 1 pathologically proven schwannoma or meningioma AND germline SMARCB1 pathogenic mutation

Clinical diagnosis:

2 or more non-intradermal schwannomas 1 with pathological confirmation No bilateral vestibular schwannoma by high-quality MRI (detailed study of internal auditory canal with slices no more than 3 mm thick). Recognize that some mosaic NF2 patients will be included in this diagnosis at a young age and that some schwannomatosis patients have been reported to have unilateral vestibular schwannomas or multiple meningiomas. One pathologically confirmed schwannoma or intracranial meningioma AND affected first-degree relative Possible diagnosis: 2 or more non-intradermal tumors but none has been pathologically proven to be a schwannoma

Imaging plays an important role in the clinical diagnostic criteria, particularly for the exclusion of NF2, by assessing for bilateral vestibular schwannomas. Whole-body magnetic resonance imaging (WB-MRI), especially at 1.5T, is a diagnostic method for the evaluation of the other NF syndromes, with an evolving role for assessing SWN.^9–18 Given that, in SWN, the natural history of tumor growth is uncertain and the tumors involve multiple body regions, WB-MRI provides an efficient means by which to monitor tumor change or new tumor formation. In addition, use of functional MRI allows for the characterization of lesions as benign or malignant, and potentially, for the assessment of treatment response. There is a paucity of information on PNST imaging characteristics by WB-MRI,^10,14,15,18 and there is limited experience with functional imaging techniques in SWN.¹⁸ With the exception of Fayad et al,¹⁸ most of the WB-MRI investigations for NF have been performed at 1.5T and focused solely on anatomic sequences comprised of a combination of T₁-weighted, fluid-sensitive, and postcontrast sequences.^9–17 Similarly, although metabolic imaging with fluorine-18-fluorodeoxyglucose positron emission tomography / computed tomography (FDG-PET/CT) has been used as an adjunct modality for the characterization of PNSTs in patients with NF1,¹² the only data about its utility in SWN is in case reports.^19,20 The purpose of this study is to describe the anatomic, functional, and metabolic characteristics of PNSTs in patients with SWN using a combination of WB-MRI (with anatomic and functional imaging) and FDG-PET/CT imaging (metabolic imaging).

Materials and Methods

Overview

Institutional Review Board (IRB) approval was obtained and informed consent was waived for this HIPAA-compliant retrospective study. Two readers reviewed WB-MRIs performed in 13 subjects with clinically or genetically confirmed SWN using anatomic (T₂ STIR, T₁-weighted, contrast-enhanced T₁-weighted), and functional (diffusion-weighted imaging [DWI] with apparent diffusion coefficient [ADC] mapping) imaging. Serial WB-MRIs and metabolic imaging with FDG-PET/CT available in a subset of patients were also reviewed. Imaging features at presentation and follow-up are described.

Subject Population

Subjects were recruited from an IRB-approved clinical database of patients seen in a specialty neuro-oncology clinic dedicated to the care of patients with NF1, NF2 and SWN. Inclusion criteria were: patients with clinically or genetically confirmed SWN who had undergone at least one WB-MRI. Exclusion criteria were patients with localized rather than WB-MRI, and patients not meeting diagnostic criteria for SWN.

MRI Technique

WB-MRI, using parallel imaging and total imaging matrix, was performed as per protocol at 1.5T (n = 3) and 3.0T (n = 10).¹⁸ Large field of view (FOV = 50 × 50 cm²) and automatic table motion were combined for a total scan range of 205 cm.¹⁸ In addition, a respiratory-gated, 2D prospective acquisition correction technique was employed to decrease respiratory motion-related artifacts.¹⁸

Anatomic imaging was comprised of pre- and postgadolinium-based contrast-enhanced T₁-weighted sequences (volume interpolated breath-hold examination [VIBE]) and fluid-sensitive (short tau inversion recovery [STIR]) sequences. The 3.0T WB-MRI parameters were as follows: pre- and postcontrast VIBE (TR/TE = 3.1–5.6/1.4–2.5 msec, matrix = 256–320 × 234–256, slice thickness = 1.5 mm) and STIR (TR/TE/TI = 2760–3000/88–342/220 msec, matrix = 256 × 256, slice thickness = 2 mm with interpolation) sequences. Similarly, the 1.5 T WB-MRI parameters were as follows: pre- and postcontrast enhanced VIBE (TR/TE 2.4/0.9 msec, matrix = 256 × 256, slice thickness = 1.5 mm) and STIR (TR/TE/TI = 3000/966/160 msec, matrix = 256 × 256, slice thickness = 2 mm with interpolation). All imaging was acquired in the coronal plane with isotropic resolution (T₁-weighted) or near-isotropic resolution (STIR), enabling multiplanar (MPR) reformations into axial and sagittal planes for interpretation.¹⁸ Subtraction imaging was also performed, with subtraction of the precontrast from the postcontrast T₁-weighted images, to increase enhancement conspicuity. Of the total of 13 subjects, six (46%) subjects had 17 follow-up WB-MRIs in addition to their baseline WB-MRI (with a follow-up range of 4 months to 45 months).

Functional MRI using quantitative DWI and ADC mapping was also performed. At 3.0T WB-DWI parameters included TR/TE = 3400–6300/60–82 msec, b values = 50, 400, 800 s/mm², averages = 4, acceleration factor = 2, slice thickness = 5 mm. Similarly, 1.5T WB-DWI parameters included TR/TE = 5800/80 msec, b values = 50, 400, 800 s/mm², averages = 4, acceleration factor = 2, slice thickness = 5 mm. Echo-planar spin-echo DWI using a free-breathing sequence was performed prior to the administration of intravenous contrast material. Three b-values were chosen to obtain an accurate ADC value.¹⁸ A quantitative ADC map was generated via manufacturer-provided software.¹⁸

PET/CT Technique

FDG-PET/CT studies on two subjects were performed according to our institutional clinical protocol. FDG-PET/CT imaging was performed on a Discovery VCT (3D) (GE Healthcare, Milwaukee, WI) LySO-crystal 64-slice scanner PET/CT or Siemens (Erlangen, Germany) Biograph mCT scanner. Patients were instructed to fast for at least 6 hours before FDG-PET imaging to standardize blood glucose and insulin levels. Blood glucose levels measured before injection of FDG ranged from 70 mg/dL to 105 mg/dL. Approximately 60 minutes before image acquisition, patients were injected with 0.21 mCi/kg of FDG. Whole-body scanning was performed, with images obtained in the supine positions with the arms above the head. For CT imaging, only oral contrast was administered. Helical CT (120 kV; 20–2,000 mAs) images were obtained with a matrix of 512 × 512. Beam collimation was 10 mm, with a pitch of 0.984. Slice thickness was 3.75 mm. The noncontrast CT scans were used for attenuation correction and localization. Non-IV-contrast CT and FDG-PET images were obtained from the vertex of the skull to the mid thighs, and then repeated from the upper thighs through the feet, as two separate acquisitions. One subject had one FDG-PET/CT scan with images acquired in early and delayed (4 hours after radiotracer administration) phases. The second subject had eight serial FDG-PET/CT scans spanning from 06/2009 to 07/2014. The initial FDG-PET/CT on 06/2009 was performed as a dual phase acquisition (with early and delayed scans) and the remainder of the examinations were performed with only the early phase of imaging.

WB-MRI Image Analysis

Two readers, one with 7 years’ experience and one with 3 years’ experience in WB-MRI interpretation, reviewed the images independently. All imaging planes were assessed (coronal as well as reconstructed axial and sagittal views). First, readers recorded the diagnostic quality for each study, by body part (chest, abdomen, pelvis, thighs, thoracic spine, lumbar spine, neck, and calves). Quality was assessed using a semiquantitative scale, ranging from 1 to 4 (1: nondiagnostic or artifacts involving more than or equal to 75% of the image; 2: artifacts involving 25–75% image; 3: artifact involving less than or equal to 25% of the image; 4: no significant artifact).¹⁸

For anatomic imaging, readers recorded imaging characteristics of the peripheral lesions including the largest lesional diameter, location (chest, abdomen, pelvis, thighs, thoracic spine, lumbar spine, neck, calves, or arms), shape (ovoid or irregular), and margin (well-defined, partly defined, ill-defined) of each peripheral lesion. A peripheral lesion was defined as any mass-like, STIR hyperintense abnormality detected on the images and confirmed on other sequences including T₁-weighted and DWI sequences. Only peripheral lesions visualized in at least two planes and greater than 1 cm in largest lesion diameter were characterized for the purpose of this analysis. Lesions were characterized as tumors or cysts based on contrast-enhancement properties (enhancement = PNST and no enhancement = cyst). The presence or absence of central or spinal canal lesions was recorded, although not included for the purposes of PNST characterization. Signal characteristics (hypointense, isointense, and hyperintense) relative to muscle, and degree of heterogeneity (homogeneous and less than 25% heterogeneous, moderately heterogeneous with 25–75% heterogeneity, and markedly heterogeneous with greater than 75% heterogeneity) were recorded on T₁-weighted images, STIR, and contrast-enhanced imaging. The presence or absence of characteristic neurogenic tumor features such as the target sign and the split fat sign were recorded, along with the presence or absence of perilesional edema.^21–23 The character of the lesion regarding its relationship to the adjacent nerve (eccentric or central) was assessed when possible.

For functional imaging assessment, the readers assessed the presence or absence of heterogeneity on the ADC map (homogeneous and less than 25% heterogeneous, moderately heterogeneous with 25–75% heterogeneity, and markedly heterogeneous with greater than 75% heterogeneity) and the presence or absence of the target sign on the ADC maps. Each reader independently constructed a circular or ovoid region of interest to encompass as much of the entire lesion as possible and recorded the minimum, average, and maximum ADC map values (with standard deviation) for each peripheral lesion.

In addition, the presence or absence of scoliosis (Cobb angle measuring greater than 15°), nerve root thickening, and incidental abnormalities unrelated to the peripheral nervous system were recorded. For 6/13 subjects with serial WB-MRIs, the change in lesion size and imaging characteristics including ADC values were recorded. For subjects with serial WB-MRIs, imaging characteristics were reviewed in tandem.

PET-CT Image Analysis

FDG-PET/CT images were also analyzed and the maximum standardized uptake value (SUV_max [g/mL]) in index lesions was recorded.

Statistical Analysis

Descriptive statistics were reported regarding subject demographics, image quality for all body locations, number of lesions, lesion location, and lesion characteristics on the anatomic and functional sequences (largest lesional diameter, signal intensity, heterogeneity, the presence or absence of specific signs described above, and ADC values). Pearson correlation was assessed for the number of peripheral nerve tumors and age. For the largest lesional diameter and ADC values, interreader reliability was assessed with intraclass correlation (ICC) and an average of the two readers’ assessments was reported. Agreement was interpreted as poor (ICC, 0–0.4), fair to good (ICC, 0.41–0.75), or excellent (ICC, >0.75). In the two cases with metabolic imaging, SUV_max for 15 index lesions for the initial and delayed examinations is reported. Changes in the lesion size, MRI characteristics, and SUV_max of the index lesions are reported in subjects with serial imaging.

Results

Thirteen subjects (mean age 45 years; range 23–61 years) with a genetic or clinical diagnosis of SWN were included. Of these, 38% (5/13) subjects were female, and 23% (3/13) had WB-MRI at 1.5T, while 77% (10/13) underwent WB-MRI at 3T. Table 2 shows the image quality for all body regions. Precontrast T₁ weighted images had the highest image quality (mean diagnostic quality score of 4), while DWI had the lowest image quality, with a mean diagnostic score of 2.8. DWI had the lowest image quality for all body parts and 33% (51/149) of lesions could not be confidently assessed on ADC maps for both readers, due to either insufficient quality (n = 43) or small lesion size (n = 8). In 23% (3/13) of patients, the upper extremities (n = 2) and distal calves (n = 1) were incompletely imaged.

TABLE 2.

Average Diagnostic Quality by Body Part and Sequence Using Whole Body-MRI

Location	T1w	STIR	T1w + contrast	DWI
Spine-chest	4.0	3.9	4.0	2.7
Spine-abdomen	4.0	4.0	4.0	2.8
Neck	4.0	4.0	4.0	2.5
Chest	4.0	4.0	4.0	2.8
Abdomen	4.0	4.0	4.0	2.8
Pelvis	4.0	3.9	3.6	3.0
Thigh	4.0	3.9	4.0	2.8
Calves	4.0	4.0	3.5	3.0
Mean	4.0	3.9	3.9	2.8

A total of 255 lesions were detected and 153 index lesions were characterized, with a median size of 2.3 cm (range 1–24.3 cm) (Fig. 1). Of the 153 index lesions, only 98 peripheral lesions were assessed on DWI. Figure 1b shows the anatomic distribution of the various peripheral nerve sheath tumors. Lesions were characterized as tumors (97%; 149/153) or cysts (3%; 4/153) (Fig. 2). The majority of PNSTs were solitary (96%; 143/149), while only 4% (6/149) were plexiform. There was a very weak positive correlation with the number of peripheral nerve tumors and increasing age (R = 0.235, Pearson correlation coefficient). Anatomic imaging features of each PNST were noted with respect to each MRI sequence (Table 3). On DWI, tumor ADC values (×10⁻³ mm²/s) were variable (minimum ADC range 0.3–2.2, average ADC range 0.9–2.9 and maximum ADC range 1–4.8) and 20% (20/98) of lesions exhibited a target sign on ADC maps (Fig. 3). In addition, interobserver agreement was greater than 0.9 for all the peripheral lesion imaging features including shape, margin, signal intensity, and heterogeneity on T₁, STIR, and postcontrast T₁ sequences, as well as for the neurogenic features (target sign, tail sign, split fat sign, relationship to the parent nerve). Interobserver agreement was also excellent for measurements made by the two readers on anatomic and functional MRI sequences (largest lesional diameter, ICC = 0.99; for the minimum ADC value, 0.95; for the average ADC value, 0.93 and for the maximum ADC value, 0.96).

FIGURE 1:

a: The frequency of PNST size across patients with schwannomatosis. Note that majority of the tumors are less than 5 cm in largest lesional diameter, although larger tumors and plexiform tumors also occur. b: The distribution of peripheral nerve tumors across body locations. c,d: The range of minimum and average ADC values in PNSTs in SWN, although minimum ADC value is used for characterization of PNSTs.⁴² e: The distribution of early and delayed SUV_max in in PNSTs in SWN.

FIGURE 2:

A 51-year-old man with schwannomatosis. Numerous PNSTs are present in addition to a 5 mm right cervical perineural cyst (long arrow) noted. (a) Coronal STIR and (b) precontrast T₁-weighted images. The perineural cyst does not demonstrate a “target sign” associated with PNSTs. (c,d) Postcontrast T₁-weighted unsubtracted and subtracted images show lack of internal enhancement of the right cervical perineural cyst in contrast to heterogeneous intralesional enhancement of a left thoracic PNST (short arrow).

TABLE 3.

Anatomic, Metabolic, and Functional Features of PNSTs in SWN

Anatomic imaging features (n = 153)
Sizea	2.3 cm (1–24.3 cm)
Margin
• Well defined	94% (143/149)
• Partly well defined	3% (5/149)
• Ill defined	1% (1/149)
T1-W
• Signal characteristics
○ Hypointense	1% (1/149)
○ Isointense	99% (148/149)
○ Hyperintense	0%
• Heterogeneity
○ < 25%	99% (148/149)
○ 25–75%	1% (1/149)
○ > 75%	0%
STIR
• Signal characteristics
○ Hypointense	0%
○ Isointense	0%
○ Hyperintense	100% (149/149)
• Heterogeneity
○ < 25%	19% (28/149)
○ 25–75%	66% (99/149)
○ > 75%	15% (22/149)
T1W +C Enhancement
○ < 25%	19% (23/123)
○ 25–75%	22% (27/123)
○ > 75%	59% (73/123)
Target sign on STIR
• Absent	33% (34/149)
• Present	77% (115/149)
Tail sign
• Absent	64% (96/149)
• Present	36% (53/149)
Split fat sign
• Absent	4% (6/149)
• Present	96% (143/149)
Relationship of lesion to parent nerve
• Central	2% (3/149)
• Eccentric	33% (50/149)
• Indeterminate	65% (96/149)
Functional imaging features (n = 98)
ADC values (×10−3 mm2/s)
• Minimuma	1.7 (0.3–2.2)
• Averagea	2.1 (0.9–2.9)
• Maximuma	2.5 (1–4.8)
Target Sign
• Absent	80% (78/98)
• Present	20% (20/98)
Metabolic imaging features (n = 15)
SUVmax – Earlya	6 (2.1–11.7)
SUVmax – Delayeda	10 (2.7–15.3)

^aMedian values are provided with range in parentheses (averaged for both readers).

FIGURE 3:

A 27-year-old man with schwannomatosis. (a) Note left axillary PNST with central hypointensity on axial T₂ STIR sequences (generated as an MPR from a coronal acquisition) denoting a “target sign.” (b) The “target sign” is made more conspicuous on the ADC map.

Regarding metabolic imaging, 15 lesions were assessed by early and delayed PET in two subjects (Fig. 4). The median SUV_max value was 6 (range 2.1–11.7) and 10 (2.7–15.3) on early and delayed imaging, respectively, with average liver SUV_max measuring 1.6 (using a 3–4 cm region of interest placed in the posterior right hepatic lobe). One of the two subjects with FDG-PET/CT had eight serial metabolic examinations and the SUV_max of 12 index lesions was variable across scans with a wide range. For example, average SUV_max was 2.6 ± 2.0 (range: 1.5–9.6) in 07/2014 and 2.2 ± 1.7 (range: 1.5–8.2) in 06/2013. Because only two subjects had both FDG-PET/CT and WB-MRI, ADC values and SUV_max values were not correlated.

FIGURE 4:

Metabolic Imaging with FDG-PET CT. A 27-year-old man with schwannomatosis. Fused FDG-PET-CT image in the coronal plane shows bilateral retroperitoneal masses with SUV_max of 5.7 on the right (long arrow) and 3.6 on the left (short arrow).

Serial MRIs showed stable lesions in 3/6 subjects and an increase in lesion size in 3/6 subjects with a follow-up range of 4–44 months. In one PNST, (1/149, 1%), malignant degeneration was prospectively suggested based on lesion size change and suspicious functional MRI characteristics (increase in size from 8.7 cm to 9.6 cm, decrease in minimum ADC values, ×10⁻³ mm²/s) from 1.4 to 0.4, and increase in SUV_max from 6 to 9.6 over 5 years; this lesion was subsequently proven to be a malignant PNST histologically (Fig. 5).

FIGURE 5:

DWI with ADC mapping in the same patient as Fig. 3 with bilateral retroperitoneal PNSTs (long and short arrows). Both masses are large and heterogeneous but the left retroperitoneal lesion (short arrow) demonstrates restricted diffusion on progressive b-values (a–c) and internal hypointense signal on the ADC map (d). Quantitatively, the minimum ADC value shows restricted diffusion measuring 0.4 × 10⁻³ mm²/s. The region of restricted diffusion was targeted for percutaneous biopsy and histologically proven as a malignancy. Functional imaging with DWI and ADC mapping may be a more useful technique for characterizing a PNST as benign or malignant when compared with metabolic imaging.

Ancillary findings on WB-MRI included nerve root thickening (3/13 patients, 23%) in the absence of measurable tumor, spinal canal tumors (15% [2/13]), and the absence of scoliosis. One subject had an indeterminate solid renal mass as well as a thyroid goiter. Additional ancillary findings included knee osseous contusions, bilateral hydroceles, lumbar spine degenerative disc disease, renal cysts, paranasal sinus mucosal thickening, and varicose veins, all in one patient each.

Discussion

SWN is a recently described clinical entity within the NF syndromes, with the first established diagnostic criteria reported in 2005.¹ Patients with SWN have the propensity to develop numerous PNSTs, similar to those with NF1 and NF2.

Although there have been prior reports on the clinical features of SWN,^8,24–38 the imaging features of this disorder have been only sparsely reported, limited to descriptions of whole-body tumor burden by anatomic imaging,^10,14,15,18 and two case reports on FDG-PET avidity.^19,20 We have expanded the description of radiological attributes of SWN using multiparametric and multimodality whole-body imaging based on MRI signal characteristics and enhancement patterns, assessment of functional characteristics with DWI/ADC, and metabolic imaging features with PET.

While there have been prior reports of SWN characteristics including tumor burden, location within the body, and volumetry, specific anatomic MRI features of the PNSTs in SWN have not been previously described in detail with respect to signal characteristics on pre- and postcontrast T₁W images and STIR sequences.^{10,14,15,18,19} According to our results, PNSTs in SWN have variable anatomic imaging features, perhaps suggestive of their variable underlying composition and biological activity. However, the majority of PNSTs in SWN share common imaging characteristics with solitary schwannomas.^21–23 They are homogeneously isointense to skeletal muscle on T₁W images, heterogeneously hyperintense on fluid-sensitive sequences, and exhibit heterogeneous contrast enhancement, features that may all be identified in solitary schwannomas. Other anatomic features that have been described with peripheral schwannomas, such as the target sign, eccentric relationship to the adjacent nerve, and a tail sign, are also present in SWN.^21–23,39

The largest series on SWN was reported by Merker et al, and showed that the legs tended to harbor the largest tumor volume, followed by the pelvis.⁸ We report a slightly different distribution of PNSTs in SWN, with the maximum number of tumors in our series located in the abdomen, brachial plexus, thoracic spine, and thighs. None of the subjects in our series had a mosaic presentation of SWN, unlike Merker et al, who reported 30% with anatomically limited or segmental disease manifestation.⁸ Plexiform schwannomas were identified in our series, in agreement with the literature.⁴⁰ However, a notable anatomic imaging feature of SWN identified in our study is peripheral nerve root thickening in 23% of our patients. SWN is clinically characterized by neuropathic pain out of proportion to measurable tumor volume, and it is possible that diffuse nerve thickening is implicated in the generation of this diffuse pain. Although scoliosis can be seen in the setting of SWN with incidences as high as 6%,⁸ our case series had a notable absence of spine curvature abnormalities, possibly due to the small sample size and/or nonanatomic imaging in the supine position.

With respect to functional MRI, the DWI/ADC features of PNSTs in SWN were highly variable, with heterogeneous ADC values ranging from 0.3 to 4.8 ×10⁻³mm²/s, perhaps indicating high variability in the biologic makeup and behavior of these tumors. Solitary peripheral schwannomas have been described to be occasionally heterogeneous by MRI, due to internal hemorrhage, mineralization, and cystic degeneration,⁴¹ although it is not clear whether the schwannomas of SWN have a similar propensity as solitary peripheral schwannomas. Demehri et al⁴² explored the utility of quantitative DWI in the characterization of PNSTs as benign and malignant and found that ADC values were an excellent discriminator of benign and malignant PNSTs in NF1, but that sporadic schwannomas had variable quantitative DWI characteristics that could mimic malignancy with low ADC values. Demehri et al attributed the low minimum ADC values within the neoplasms to high cellularity and hence increased risk of malignancy.⁴² It is unclear whether malignant PNSTs in SWN would also routinely exhibit low ADC values, as there are limited data with regard to functional imaging in this patient population. Of note, the 14/22 benign peripheral nerve tumors in their investigations were sporadic schwannomas, none in the setting of schwannomatosis.⁴²

Although the majority of the PNSTs are benign and solitary, PNSTs, particularly in the setting of neurogenetic syndromes, can rarely undergo malignant degeneration. There is a 10% lifetime risk of occurrence of malignant PNST in patients with NF1.⁴³ However, malignant degeneration of schwannomas in patients with SWN has only been rarely reported (n = 3).^4,44 Our series also includes a case of malignant degeneration of a PNST in SWN, identified by anatomic and functional imaging features. While rare, the occurrence of malignancy within SWN raises an important issue of surveillance in these patients. Metabolic imaging with FDG-PET/CT is a consideration for surveillance, but schwannomas are well-known mimickers of malignancy by metabolic imaging, as they can be FDG-avid.^19,20,45,46 Specifically, in this report, one of the subjects with early and delayed acquisition FDG-PET/CT had overall high levels of SUV_max on the early acquisition (mean of 6.7, range 3.4–11.7), with a progressive rise in the delayed acquisition (mean of 10.4, range 5.4–15.3) within benign PNSTs. Case reports of metabolic imaging of schwannomas in the setting of SWN suggest FDG avidity with elevated SUV values ranging from 4.3–6.3 in benign schwannomas.^19,20 As such, due to the high metabolic activity observed in benign PNSTs by PET imaging in SWN, WB-MRI with functional sequences may be a more suitable and economic technique for the assessment of tumor behavior over time.

The limitations of this study include the small sample size, population bias, and retrospective nature. Additionally, WB-MRI coverage of the calves and upper extremities can be limited in taller individuals, as noted in 23% (3/13) of the cases in our series. DWI, due to intrinsically lower spatial resolution, eddy currents, variable shimming, and chemical shift artifacts had the lowest image quality for all body parts, and subsequently a small quantity of lesions could not be confidently assessed on ADC maps. Also, the coronal image acquisition and large FOV also likely affected the DWI image quality. An additional limitation includes heterogeneity in the WB-MRI protocol among patients, as a small proportion of the subjects were imaged at 1.5T rather than 3.0T. Although this likely does not affect the anatomic imaging features, it may impact the ADC values obtained from the two different techniques. Another limitation is that tumors were measured manually in one plane, rather than volumetrically, as in other studies.^10,14,15 This may have resulted in underreporting of change in tumor size over time. In addition, serial WB-MRI or PET/CT examinations were not available in all subjects; hence, the range of metabolic characterization of schwannomas in this group of patients may be underrepresented.

In conclusion, PNSTs in SWN can have variable anatomic, functional, and metabolic characteristics, showing high ADC values by DWI and high metabolic activity by PET. Patients with SWN also exhibit peripheral nerve root thickening that may be suggestive of peripheral neuropathy. Although the majority of the PNSTs are benign and solitary, PNSTs in SWN can be plexiform in nature, enlarge over time, and, rarely, undergo malignant degeneration. Due to the high metabolic activity observed in benign PNSTs by FDG-PET imaging in SWN, WB-MRI with functional sequences may be a more suitable alternative for the determination of tumor burden, characterization of the PNSTs, and surveillance over time.