nonenhancing peritumoral hyperintense lesion on diffusion ... · diffusion-weighted mri enables...

CLINICAL ARTICLEJ Neurosurg 128:667–678, 2018

Glioblastoma is the most common malignant pri-mary neoplasm of the CNS,22,31 accounting for 16% of all primary intracranial tumors and 54% of

all gliomas.31 Brain metastases and malignant lymphoma are the most common entities in the differential diagnosis

for glioblastoma, often with indiscernible characteristics on MRI. Brain metastases may present either as solitary (approximately 30% of patients)3,33 or as multiple lesions and are difficult to distinguish from multiple high-grade or multicentric gliomas since both may exhibit ring enhance-

ABBREVIATIONS ADC = apparent diffusion coefficient; ADCMIN = minimum absolute ADC; BBB = blood-brain barrier; CNWM = contralateral normal white matter; DTI = dif-fusion tensor imaging; DWI = diffusion-weighted imaging; IDH-1 = isocitrate dehydrogenase 1; KPS = Karnofsky Performance Scale; NePDHL = nonenhancing peritumoral DWI high lesion; ROI = region of interest; RPA = recursive partitioning analysis; SIR = signal intensity ratio; T1WI = T1-weighted imaging; T2*WI = T2*-weighted imaging. SUBMITTED June 28, 2016. ACCEPTED October 21, 2016.INCLUDE WHEN CITING Published online March 31, 2017; DOI: 10.3171/2016.10.JNS161694.

Nonenhancing peritumoral hyperintense lesion on diffusion-weighted imaging in glioblastoma: a novel diagnostic and specific prognostic indicatorManish Kolakshyapati, MD,1 Rupendra B. Adhikari, MD, PhD,1 Vega Karlowee, MD,1 Takeshi Takayasu, MD, PhD,1 Ryo Nosaka, MD,1 Vishwa J. Amatya, MBBS, PhD,2 Yukio Takeshima, MD, PhD,2 Yuji Akiyama,3 Kazuhiko Sugiyama, MD, PhD,4 Kaoru Kurisu, MD, PhD,1 and Fumiyuki Yamasaki, MD, PhD1

Departments of 1Neurosurgery, 2Pathology, 3Clinical Radiology, and 4Clinical Oncology and Neuro-oncology Program, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

OBJECTIVE Glioblastoma differentials include intracranial tumors, like malignant lymphomas and metastatic brain tumors with indiscernible radiological characteristics. The purpose of this study was to identify a distinct radiological feature for the preoperative differentiation of glioblastoma from its differentials, which include malignant lymphomas and metastatic brain tumors.METHODS Preoperative MR images, including diffusion-weighted imaging (DWI) studies (b = 1000 and 4000 sec/mm2), obtained in patients with newly diagnosed malignant tumor, were analyzed retrospectively after receiving approval from the institutional review board. Sixty-four patients with histologically confirmed glioblastoma, 32 patients with malignant lymphoma, and 46 patients with brain metastases were included. The presence of a nonenhancing peritumoral DWI high lesion (NePDHL, i.e., hyperintense lesion in a nonenhancing peritumoral area on DWI) was confirmed in both DWI sequences. Gray matter lesions were excluded. Lesions were termed “definite” if present within 3 cm of the hyperin-tense tumor border with a signal intensity ratio ≥ 30% when compared with the contralateral normal white matter in both sequences. Discriminant analysis between the histological diagnosis and the presence of Definite-NePDHL was per-formed, as well as Kaplan-Meier survival analysis incorporating the existence of Definite-NePDHL.RESULTS In 25% of glioblastoma patients, Definite-NePDHL was present, while it was conspicuously absent in patients with malignant lymphoma and metastatic brain tumors. The specificity and positive predictive value were 100%. In the glioblastoma subset, a higher preoperative Karnofsky Performance Scale score (p = 0.0028), high recursive partitioning analysis class (p = 0.0006), and total surgical removal (p = 0.0012) were associated with better median overall survival. Patients with Definite-NePDHL had significantly early local (p = 0.0467) and distant/dissemination recurrence (p < 0.0001) and poor prognosis (p = 0.0007).CONCLUSIONS The presence of Definite-NePDHL is very specific for glioblastoma and indicates poor prognosis. Def-inite-NePDHL is a significant indicator of early local and distant/dissemination recurrence in patients with glioblastoma. Studying peritumoral DWI and high–b-value DWI is useful for tumor differentiation.https://thejns.org/doi/abs/10.3171/2016.10.JNS161694KEY WORDS glioblastoma; DWI; high b-value; peritumoral region; diffusion restriction; oncology

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M. Kolakshyapati et al.

J Neurosurg Volume 128 • March 2018668

ment and extensive edema.33 Primary CNS lymphomas, particularly those of B-cell origin, may be confused with glioblastomas or brain metastases. Diverse management protocols and prognosis entail preoperative differentiation among these entities.3,33

Diffusion-weighted MRI enables volumetric intravoxel measurement of tissue characteristics.38 Using diffusion-weighted imaging (DWI) for the diagnosis of brain tu-mors has been previously investigated, and its value for tumor differentiation has been reported.12,16,17,21,33,37 Earlier diffusion tensor imaging (DTI) and DWI studies focused mostly on tumors,2,7,10,27,36–38 and only a few included the peritumoral region.12,16,17,20,21,25,26 Most studies have consid-ered the area surrounding the enhanced tumor as the pe-ritumoral region,12,13,17,20,37,38 while Wang et al. divided this area into the immediate and distant peritumoral regions.33 Studies focusing on DTI and the apparent diffusion coef-ficient (ADC) of the peritumoral white matter have report-ed conflicting results, and even those with positive results have considerable overlap.12,17,20,23,25,33 Studies focusing on diffusion restriction as a poor prognostic marker of glio-blastoma have been reported,9,11 but their use as a marker for the differentiation of glioblastoma has not been con-clusively reported. Other advanced MRI studies, including MR spectroscopy and perfusion-weighted imaging stud-ies, have also reported similar overlapping results when used independently for tumor differentiation.2,3,13

Glioma cells originating from the brain itself are known to infiltrate beyond the visible margins of the Gd-enhanced tumor on MRI and potentially invade the surrounding white matter, specifically along the vascular channels and white matter tracts without blood-brain barrier (BBB) disruption.26,27 This increases tissue cellularity, resulting in hyperintensity on DWI.3,27,40 This region may be non-enhancing until characteristic and highly permeable neo-vascularization occurs.13,26 Hence, nonenhancement does not imply the absence of infiltration into the peritumoral region.26,34 On the contrary, noninfiltrative tumors—i.e., malignant lymphomas and brain metastases—disrupt the BBB and contrast enhancement represents tumor tissue, while peritumoral T2 hyperintensity indicates vasogenic edema.6,34 Conventional MRI fails to differentiate micro-scopic tumor–infiltrated peritumoral tissue from vasogen-ic edema, as both appear as nonenhancing hyperintensity on T2-weighted imaging.15,26 Imaging based on molecular physiology, like DWI and ADC, can further characterize and differentiate tumors according to the characteristics of the tumor borders and peritumoral tissue.26

In our study, we focused on peritumoral white matter on DWI to establish its usefulness for differentiating glio-blastoma from malignant lymphoma and brain metastases and identify a feature that is efficient for its preoperative differentiation.

MethodsPatients

This retrospective study was conducted after receiv-ing approval from the institutional review board, which waived the need for informed consent. Patients who un-derwent surgical resection at our institute were included.

Preoperative MR DWI at 3T with b = 1000 sec/mm2 and b = 4000 sec/mm2 were reviewed in 142 histologically con-firmed patients. HIV-positive and immunocompromised patients and those who had undergone previous surgery, chemotherapy, radiotherapy, or radiosurgery were exclud-ed. Patients with acute/subacute ischemia, as evident by the presence of the clinical signs and symptoms consistent with ischemic stroke, gliosis, or chronic infarction, were excluded.

Among 64 patients with glioblastoma, 37 men and 27 women (mean age 60.8 years; median 64.5 years; range 11–85 years) had newly diagnosed glioblastoma (WHO Grade IV). Thirty-two patients with malignant lympho-ma (15 men and 17 women; mean age 67.2 years; median 68.5 years; range 26–83 years) had primary diffuse large cell B-lymphoma. Similarly, 46 patients with metastatic tumors (26 men and 20 women; mean age 66.4 years; me-dian 69.0 years; range 19–90 years) had metastases from the lung, colon, kidney, breast, stomach, bone, and skin.

MRIAll MRI studies were performed using a 3-T super-

conducting system (Signa Excite HD 3.0T; GE Medical Systems). Preoperative MRI included T2-weighted imag-ing (TR 4800 msec, TE 100 msec, echo train length 18, FOV 22 × 22 cm, matrix size 512 × 320, NEX 2, section thickness 6 mm, intersection gap 1.0 mm, 1 acquisition) or FLAIR (TR 10,000 msec, TE 140.0 msec, inversion recov-ery time 2400.0 msec, FOV 22 × 22 cm, matrix size 288 × 160, NEX 1, section thickness 6 mm, intersection gap 1.0 mm, 2 acquisitions), and T2*-weighted imaging (T2*WI) (TR 600.0 msec, TE 12 msec, FOV 22 × 22 cm, matrix size 320 × 192, NEX 1, section thickness 6 mm, intersection gap 1.0 mm, 1 acquisition). Axial spin-echo T1-weighted imaging (T1WI) was performed with the following param-eters: TR 450 msec, TE 18 msec, FOV 18 × 18 cm, matrix size 288 × 192, section thickness 6 mm, intersection gap 1.0 mm, 2 acquisitions. Contrast-enhanced T1WI was per-formed after the intravenous administration of 0.1 mmol/kg body weight of the Gd-based contrast medium.

DWI was performed with b-values of 1000 and 4000 sec/mm2 with an effective gradient 40 mT/m and slew rate of 150 mT/m/msec. The parameters were as follows: 8-channel phased-array head coil; TR 5000 msec and TE 73.2 msec (b-1000); TR 5000 msec and TE 100 msec (b-4000); NEX 1; FOV 22 × 22 cm; slice thickness 6 mm; intersection gap 1.0 mm; 20 slices; data acquisition matrix 128 × 128; 2 acquisitions. The scan times were 20 and 40 seconds for b-1000 and b-4000, respectively. Images with b = 0 sec/mm2 were obtained simultaneously. DWI at these b-values is routinely performed at our institution according to an institutional protocol that favors the use of these b-values.

Peritumoral Region and Nonenhancing Peritumoral DWI High Lesions

The area adjacent to and within 3 cm of the enhanced tumor was defined as the peritumoral region. The presence of a nonenhancing peritumoral DWI high lesion (NeP-DHL; i.e., hyperintense lesion in a nonenhancing peritu-


Nonenhancing peritumoral DWI high lesion in glioblastoma

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moral area on DWI) was first investigated on DWI with b = 1000 sec/mm2 and compared with DWI with b = 4000 sec/mm2 on slices at the same level. The presence or ab-sence of enhancement was investigated on Gd-enhanced T1WI. NePDHL was confirmed on both DWI sequences by 2 observers individually and then in consensus.

Defining the LesionsLesions were defined based on DWI with both b = 1000

and b = 4000 sec/mm2. Higher b-value DWI is more effec-tive, but the signal-to-noise ratio is poor and requires the use of regular–b-value DWI to confirm the data.

DWI hyperintensity may be due to restricted diffusion or other artifacts, including the T2-shine-through effect in normal tissue. Differentiating between strongly hyperin-tense and mildly hyperintense signals on DWI by visual inspection alone is sometimes difficult. In our study, set-ting the signal intensity ratio (SIR) of the DWI signal in-tensity at 30% had a sensitivity of 1 and specificity of 0.8 (area under the curve 1) and could delineate between the actual hyperintensity of NePDHL and those arising due to artifacts and the T2-shine-through effect of the longer T2 relaxation time of normal white matter.

All gray matter and basal ganglia lesions were exclud-ed, as DWI shows a hyperintense signal in normal and compressed gray matter. The T2-shine-through effect, which may be confused with the lesion, was carefully ex-cluded using ADC maps. After confirming the presence of NePDHL, lesions were termed “definite” (Definite-NePDHL) if present within 3 cm of the enhanced tumor as a hyperintensity with a SIR of ≥ 30% compared with contralateral normal white matter (CNWM) on both se-quences. They were termed “probable” (Probable-NeP-DHL) if present on only 1 DWI sequence (SIR ≥ 30%) or present with an SIR of < 30% on both sequences com-pared with CNWM.

ADC Mapping and CalculationAll data were processed using a GE Advanced Work-

station (GE Medical Systems), and the ADC maps were generated using software (Functool, GE Medical Sys-tems). For DWI at different b-values (0 and 1000 sec/mm2 for the ADC maps at b = 1000 sec/mm2, and 0 and 4000 sec/mm2 for the ADC maps at b = 4000 sec/mm2), the maps were obtained on a pixel-by-pixel basis.

Regions of interest (ROIs) in the enhanced tumor and Definite-NePDHL on the ADC maps of b = 1000 sec/mm2 were manually placed in consensus. The same pro-cess was repeated for ADC maps of b = 4000 sec/mm2 with ROIs of the same size in the same location. The size of the tumor determined the number of ROIs that were placed. Lesion capsules and cystic, necrotic, and hemor-rhagic regions that might influence the ADC values were avoided. Cystic regions were differentiated on T2-weight-ed MR and FLAIR images as hyper- and hypointense areas, respectively. Necrotic regions were differentiated as the nonenhancing interior of the enhanced lesions on Gd-enhanced T1WI. Hemorrhagic areas were focal areas of hyper- and hypointensity on nonenhanced T1WI and T2*WI, respectively.

The ADC values (b = 1000 sec/mm2) of Definite- NeP-DHL were compared with those of CNWM. One patient had inadequate DWI data and was excluded from the ADC studies. The ADC values of Definite-NePDHL, CNWM, and the tumor were expressed as the minimum absolute ADC values (ADCMIN), as defined as the minimum ADC value among the mean ADC values determined from mul-tiple ROIs.

Histopathological StudyTumor specimens obtained after either biopsy or resec-

tion were fixed in 10% phosphate-buffered formalin and embedded in paraffin blocks. Representative slides were then stained with a hematoxylin and eosin reagent for standard histological diagnosis according to WHO crite-ria19 in consensus by 2 authors who were blinded to all clinical and radiological data.

IDH-1 Mutational StatusMutant isocitrate dehydrogenase 1 (IDH-1) immuno-

histochemical staining was performed on all glioblasto-ma samples, as described previously.14 All samples were stained in an automated immunostainer (BenchMark GX, Ventana) using the ultraView universal DAB detection kit (Ventana). Antigen-unmasking treatment was performed with standard Cell Conditioning 1 (Ventana). Anti–hu-man IDH1 R132H (1:20 dilution; Dianova) was used as the primary antibody with incubation performed at 37°C for 32 minutes. Mutant IDH-1 was considered positive when there was strong cytoplasmic staining.

Statistical AnalysisStatistical analyses were performed using SAS (version

9.1, SAS Institute). The survival time of the glioblastoma patients was measured from the time of surgery to the time of death or last follow-up (range 4.6–96.5 months; median 19.6 months). Three patients did not receive any postop-erative adjuvant therapy (concomitant radiotherapy and temozolomide) and were excluded from the survival anal-ysis. The factors analyzed as potential prognostic mark-ers included age, sex, duration of symptoms, preoperative Karnofsky Performance Scale (KPS) score, extent of sur-gery, recursive partitioning analysis (RPA) class, and pres-ence of Definite-NePDHL. According to the proportion of tumor removed as evident on Gd-enhanced MRI that was performed within the 1st postoperative week, the extent of surgery was categorized as total removal (> 99%), subtotal removal (96%–99%), partial removal (50%–95%), or bi-opsy (≤ 50%). Only the Gd-enhanced portion of the tumor was resected. Definite-NePDHL was not removed as these were not considered tumor residue. For postoperative radi-ation therapy, Definite-NePDHL was included in the irra-diation field and received an equal dose of radiation as the enhanced tumor because it was adjacent to the enhanced tumor. The treatment results were evaluated using RPA.18 We categorized RPA Classes 3 and 4 as Group 1 and RPA Classes 5 and 6 as Group 2.

Univariate and multivariate analyses of specific prog-nostic indicators were performed. Kaplan-Meier survival analysis (using the log-rank test), which incorporated the




presence of Definite-NePDHL, was performed to evalu-ate the prognostic value in glioblastoma patients. Multiple regression analysis with the Cox proportional hazards modeling was applied to assess the influence of prognos-tic factors.

Glioblastoma recurrence was defined based on the RANO (Response Assessment in Neuro-Oncology) crite-ria.35 The dates and time intervals of recurrence during the follow-up period after the initial surgery were noted. Glioblastoma recurrence was categorized as follows: lo-cal, if it appeared at or near the primary tumor; distant, if it appeared at distant sites irrespective of the primary tumor; or dissemination, if it occurred at sites adjacent to the CSF spaces after initial treatment. Distant and/or dis-semination recurrence were defined based solely on MRI. The log-rank test was performed to assess the association between the presence of Definite-NePDHL and the time interval of tumor recurrence. For all statistical results, sig-nificance was assigned when the p value was < 0.05.

Illustrative CasesCase 1

A 64-year-old, right-handed man presented with the complaints of a severe, incapacitating headache and slight disturbances in memory function for 3 weeks. He also had a history of road traffic accident because of hemianopia. On examination, he had left hemiparesis. MRI revealed a huge enhancing mass in the right cerebral hemisphere with cystic and hemorrhagic components. Postcontrast images showed no enhancement in the peritumoral region, which demonstrated high signal intensity on DWI at b = 1000 sec/mm2 and b = 4000 sec/mm2 with an SIR of > 30% on both sequences when compared with the CNWM. This lesion was defined as Definite-NePDHL. The pa-tient underwent surgical excision of the mass, and a histo-pathological study confirmed the mass to be glioblastoma (WHO Grade IV).

Case 2A 63-year-old man presented with the complaints of

progressive motor aphasia and fatigue for 3 months. MRI revealed multiple ring-enhancing lesions in the left ce-rebral hemisphere with the differential diagnosis includ-ing multiple brain metastases, malignant lymphoma, and glioblastoma. Postcontrast images showed a nonenhanc-ing peritumoral region, which appeared as high signal intensity on DWI at b = 1000 sec/mm2 and b = 4000 sec/mm2 with an SIR > 30% on both sequences compared with CNWM. This represented another positive case of Definite- NePDHL. The patient underwent craniotomy and excision of the lesion. Histopathology confirmed the lesion to be glioblastoma (WHO Grade IV) (Fig. 1).

Case 3A 60-year-old man presented with a history of blurred

vision and floaters in the eye. He visited an ophthalmolo-gist and was diagnosed with uveitis. On examination, he had photophobia and mild cognitive impairment. MRI of the brain revealed a strongly enhancing mass involving the splenium of the corpus callosum. Postcontrast MRI

showed an enhanced mass with a nonenhanced peritu-moral region. The same area demonstrated slightly high signal intensity on DWI at b = 1000 sec/mm2 and b = 4000 sec/mm2, but this did not fulfill the criteria of an SIR > 30% compared with CNWM. This lesion was defined as Probable-NePDHL. Histopathological study of the biopsy specimen from the mass confirmed it as a malignant lym-phoma (Fig. 2).

ResultsPatient Characteristics and ADC Values of Different Tumors

The patient characteristics are summarized in Table 1. Patient ages ranged from 11 to 85 years (mean ± SD 60.8 ± 14.16 years; median 64.5 years). The glioblastoma pa-tients were categorized based on prognostic factors such as sex (37 male and 27 female patients), age (11 patients were < 50 years and 53 patients were ≥ 50 years), duration of symptoms (53 patients had symptoms for < 3 months and 11 patients had symptoms for ≥ 3 months), KPS (38 patients had a score ≤ 70 and 26 patients had a score ≥ 80), extent of surgery (24 patients underwent total removal and 40 patients underwent nontotal removal, which included subtotal and partial removal and biopsy), RPA class (34 patients were RPA Class 3 or 4 and 30 patients were RPC Class 5 or 6), and Definite-NePDHL (48 patients were negative and 16 patients were positive).

Multiple regression analysis was performed between the groups in Table 1, and the results are summarized in Table 2 and Fig. 3. Age was a significant differentiating factor between different tumor groups (malignant lym-phoma vs glioblastoma, and glioblastoma vs metastatic brain tumor), as shown in Table 2. The b-value of DWI was also a significant factor (malignant lymphoma vs glio-blastoma, p < 0.01 [b = 1000 sec/mm2] and p < 0.0001 [b = 4000 sec/mm2]; glioblastoma vs metastatic brain tumor, p < 0.05 [b = 1000 sec/mm2] and p < 0.01 [b = 4000 sec/mm2]), while sex was nonsignificant.

Comparison at b = 1000 sec/mm2 and b = 4000 sec/mm2 demonstrated that the ADCMIN values of glioblasto-mas were higher than those of malignant lymphomas (p < 0.0001 and p < 0.0001, respectively; Mann-Whitney U-test) (Fig. 3A and B). Similarly, the ADCMIN values of the metastatic brain tumors were higher than those of malig-nant lymphomas at both b = 1000 sec/mm2 (p = 0.0032) and b = 4000 sec/mm2 (p = 0.0024). ADCMIN at b = 1000 sec/mm2 showed no difference between glioblastoma and metastatic brain tumors, while at b = 4000 sec/mm2 the ADCMIN values of glioblastomas were higher than those of metastatic brain tumors (p = 0.0015). However, a varying degree of overlap among glioblastomas, malignant lym-phomas, and metastatic brain tumors at both b-values was present. The association between the presence of Definite-NePDHL and the ADC value of glioblastoma was insig-nificant.

Presence of Definite NePDHLDefinite-NePDHL was present in 25% (16 of 64)

of patients with glioblastoma, with a sensitivity of 25% (95% CI 15.02%–37.40%), specificity of 100% (95% CI




95.38%–100%), positive predictive value of 100% (95% CI 79.41%–100%), and negative predictive value of 61.9% (95% CI 52.83%–70.41%).

Probable-NePDHL was present in 3 patients with ma-lignant lymphoma and an SIR > 30% on only 1 DWI se-quence (b = 4000 sec/mm2), and in 4 patients high inten-sity on DWI was observed but the SIR was < 30% on both sequences (Tables 3 and 4). Both Definite- and Probable-NePDHL were absent in all patients with multiple brain metastases.

ADC Values of Definite NePDHL and CNWMThe ADC values of Definite-NePDHL and CNWM are

summarized in Table 5. The ADC (b = 1000 sec/mm2) of Definite-NePDHL ranged from 0.533 × 10-3 to 1.02 × 10-3 mm2/sec (mean ± SD 0.713 ± 0.165 × 10-3 mm2/sec; medi-an 0.655 × 10-3 mm2/sec), and that of CNWM ranged from 0.681 × 10-3 to 1.11 × 10-3 mm2/sec (mean ± SD 0.868 ± 0.113 × 10-3 mm2/sec; median 0.852 × 10-3 mm2/sec). The ADC values of Definite-NePDHL were low compared with ADC of CNWM in all except 4 patients (p = 0.0261; Mann-Whitney U-test).

Prognostic Value of Definite NePDHL and Other FactorsUnivariate and multivariate analyses were performed to

evaluate the significance of the prognostic factors on over-all survival (Table 6). The presence of Definite-NePDHL is a significant prognostic factor for decreased survival (p = 0.0007), with a median overall survival of 11.9 months (Fig. 4B). The preoperative KPS score (p = 0.0028; Fig. 4A) and total surgical removal (p = 0.0012; Fig. 4C) were also significant. The survival analysis for glioblastoma as stratified by RPA classification showed a significant dif-ference in overall survival between Group 1 (23.9 months) and Group 2 (14.0 months) (p = 0.0006; log-rank test) (Fig. 4D). Sex, age, and duration of symptoms were nonsignifi-cant indicators.

Multivariate analysis with Cox proportional hazards modeling (Table 6) showed nontotal tumor removal as the single-most important poor prognostic factor (p = 0.0351). The results also confirmed the presence of Definite- NeP-DHL to be a poor prognostic indicator (p = 0.0420). Other factors did not show a significant association with overall survival.

Survival Analysis of Patients With Local and Distant/Dissemination Recurrence

The univariate analysis with the log-rank test cor-roborates the presence of Definite-NePDHL as a predic-tor of the early recurrence of glioblastoma (p = 0.0004)

FIG. 1. Upper: Case 1. MR images obtained in a patient with glioblastoma (WHO Grade IV) with cystic and hemorrhagic compo-nents. FLAIR (A) and postcontrast MR (B) images showing the nonenhanced peritumoral region (arrow). The same nonenhancing peritumoral region showing high signal intensity on DWI at b = 1000 sec/mm2 (C) and b = 4000 sec/mm2 (D) (arrow). This lesion was defined as a Definite-NePDHL. Lower: Case 2. MR images obtained in a patient with multiple lesions in the left cerebral hemisphere with the differentials being multiple brain metastases or malignant lymphomas. FLAIR (A) and postcontrast (B) images showing a nonenhancing peritumoral region (arrow). The same area (arrow) is seen as a high signal intensity lesion on DWI at b = 1000 s/mm2 (C) and b = 4000 s/mm2 (D). This represents a case positive for Definite-NePDHL. The lesion was also histologically confirmed to be glioblastoma (WHO Grade IV).




(Fig. 5A), with a progression-free survival of 4.9 months compared with 10.5 months in patients who were negative for Definite-NePDHL. We next analyzed the recurrence pattern of glioblastoma with a focus on the presence of Definite-NePDHL. Our results did not confirm Definite-NePDHL as the main site for recurrence. Patients with Definite-NePDHL had earlier local recurrence compared

with patients without Definite-NePDHL (5.9 months vs 11.3 months, respectively; p = 0.0467; log-rank test) (data not shown). In patients with Definite-NePDHL, the median time to distant/dissemination recurrence was 7.2 months compared with 29.4 months in patients without Definite-NePDHL, affirming the presence of this lesion as a signifi-cant indicator for early distant/dissemination recurrence in

FIG. 2. Case 3. MR images obtained in a case of malignant lymphoma of the brain. FLAIR (A) and postcontrast MR (B) images showing a nonenhanced peritumoral region (arrows). The same area is seen as high signal intensity on DW images at b = 1000 sec/mm2 (C) and b = 4000 sec/mm2 (D) (arrows), but does not fulfill the criteria of SIR > 30% compared with the CNWM. This le-sion was defined as Probable-NePDHL.




glioblastoma patients (p < 0.0001; Fig. 5B). Patients in the glioblastoma subset were classified into 2 groups: Definite-NePDHL–positive or Definite-NePDHL–negative groups. Logistic regression analysis was performed and included various determinants that showed no statistical difference between these 2 groups in terms of age, sex, KPS score, symptom duration, RPA classification, ADCMIN values, or IDH-1 mutational status (Table 7). Total resection was ob-tainable in 1 patient with Definite-NePDHL, and in the remaining 15 cases only nontotal resection was obtained (p = 0.014).

DiscussionOur study results identified Definite-NePDHL as an

exclusive radiological feature of glioblastoma and utilized the advantage of high–b-value DWI in differentiating glioblastoma. Definite-NePDHL has high specificity and a positive predictive value of 100% in differentiating glio-blastoma from malignant lymphoma and brain metastasis on preoperative MR scans.

Diffusion restriction was present in a quarter of glio-blastoma patients and was consistent with the study report-ed by Gupta et al.11 Definite-NePDHL was conspicuously absent in all cases of malignant lymphoma and metastatic brain tumors. Enhanced hyperintense lesions on DWI—called daughter lesions or lobular-type tumors—were ob-served in a few cases of malignant lymphoma and glio-blastoma. In 7 cases of malignant lymphoma, Probable-NePDHL was seen. CNS lymphoma being a whole-brain disease, Probable-NePDHL was present at distant sites as well but did not fulfill the criteria of SIR > 30% compared with CNWM to be termed “definite.” Unlike primary brain tumors like glioblastoma, malignant lymphoma, although being relatively noninvasive, is nonnative to the brain and evokes a stronger and early edematous reaction in the peritumoral region. Relatively fewer tumor cells with preservation of the underlying neuroarchitecture/white matter tracts coupled with/without early edema in the peritumoral region might explain Probable-NePDHL.

Probable-NePDHL was present in a few patients with malignant lymphoma. High–b-value DWI could be used to conclusively resolve any NePDHL ambiguity in such cases. DWI with b = 1000 sec/mm2 has been thought to be

sufficient to visualize fast- and slow-diffusion changes in water protons and is widely used, thereby generating the term “regular–b-value DWI” for b =1000 sec/mm2.7 At b = 1000 sec/mm2, diffusion within the brain is considered to be monoexponential, but increasing the b-value to 4000 sec/mm2 reveals a biexponential response.7,16,24 Fast diffu-sion corresponds to extracellular diffusion and dominates at low b-values, while slow diffusion represents intracellu-lar diffusion and is reflected at higher b-values.7,16,24 Thus, by increasing the b-value, the ADC of the white matter becomes progressively lower than that of the gray matter; i.e., the intensity of the gray matter is higher at b = 1000 sec/mm2 while the intensity of the white matter is higher at b = 4000 sec/mm2. DWI and ADC at different b-val-ues reflect different metrics. DWI performed at a b-value greater than 4000 sec/mm2 may accentuate the anisotropic effects in the brainstem and white matter and increase the acquisition time to overcome the signal-to-noise problems. These factors do not favor further increasing the b-value. Doskaliyev et al. have reported that ADC at b = 4000 sec/mm2 corroborates more significantly with tumor cellular-ity than at b = 1000 sec/mm2.7 Previous studies have also

TABLE 1. Summary of patients

Variable GBM Malignant Lymphoma Metastatic Brain Tumor

No. of patients (M/F) 64 (37/27) 32 (15/17) 46 (26/20)Mean age ± SD (range) in yrs 60.8 ± 14.7 (11–85) 67.2 ± 11.6 (26–83) 66.4 ± 15.2 (19–90)Median age (M/F) 64.5 (65/64.2) 68.5 (68/69) 69 (69/69)Definite NePDHL Present (M/F) 16 (12/4) 0 0 Absent (M/F) 48 (25/23) 32 (15/17) 46 (26/20)Mean ADCMIN ± SD (range)* b-1000 0.885 ± 0.186 (0.591–1.51) 0.732 ± 0.226 (0.432–1.34) 0.836 ± 0.221 (0.457–1.4) b-4000 0.541 ± 0.089 (0.401–0.812) 0.429 ± 0.127 (0.26–0.771) 0.481 ± 0.107 (0.259–0.782)

GBM = glioblastoma.* ADC values expressed as ×10−3 mm2/sec.

TABLE 2. Logistic regression analysis

Tumor TypePPV,

%

p Value on Multiple Regression Analysis

Age Sexb-value of

DWI

ADC b-1000 Malignant lymphoma vs GBM 74.2 <0.05* NS <0.01* Malignant lymphoma vs meta-

static brain tumor60.8 NS NS NS

Metastatic brain tumor vs GBM 64.5 <0.05* NS <0.05*ADC b-4000 Malignant lymphoma vs GBM 82.6 <0.05* NS <0.0001* Malignant lymphoma vs meta-

static brain tumor61.6 NS NS NS

Metastatic brain tumor vs GBM 67.6 <0.05* NS <0.01*

NS = not significant; PPV = positive predictive value.* p < 0.05.




reported the advantage of high–b-value DWI for different brain pathologies.1,5,8,29,41 We also recommend the routine use of high–b-value DWI for all brain MRI studies.

The ADC values (b = 1000 sec/mm2 and b = 4000 sec/mm2) of glioblastoma and metastatic brain tumor were consistently higher compared with malignant lymphoma. Similarly, the ADC values (b = 4000 sec/mm2) of glioblas-toma were higher than those of metastatic brain tumors, which were consistent with other studies.7,15,20,25,37 The ADC values from higher b-value examinations are more applicable for differentiating malignant lymphoma from glioblastoma with a positive predictive value of 82.6% (Table 2), which has already been reported.7 Although the mean ADC values of these tumors were different, indi-vidual tumors have some overlap within a narrow spec-trum. Tumor heterogeneity, difficulty in selecting the pe-

ritumoral region, infiltration by the invading tumor cells, and subjective error in the selection of ROIs may have resulted in the overlapping of values. This renders the ex-clusive use of ADC for tumor differentiation unreliable. Definite-NePDHL, on the other hand, is specific enough for the definite diagnosis of glioblastoma in individual cas-es. Furthermore, detecting Definite-NePDHL around the peritumoral region is less liable to interobserver variabil-ity, as evidenced by the lack of considerable differences in the number of cases identified separately by the observers (aided by a cutoff value of SIR at 30%) and when reexam-ined together. Amid all of the conflicting results, our study acknowledges the usefulness of DWI for differentiating glioblastoma. The peritumoral T2 hyperintense region in the glioblastoma is an area with increased intra- and ex-tracellular water and a different fractional composition of

FIG. 3. Parallel box plots showing the ADCMIN values at b = 1000 sec/mm2 (A) and b = 4000 sec/mm2 (B) in patients with glioblas-toma (GBM), malignant lymphoma (ML), and brain metastases (Mets). Each box shows the 25th to 75th percentile and median value, and the whiskers show the range.

TABLE 3. SIRs of Definite NePDHL and CNWM on DWI

Sample No.

Histological Diagnosis

b-1000 b-4000Signal Intensity on DWI

SIR Signal Intensity on DWI

SIRDefinite-NePDHL CNWM Definite-NePDHL CNWM

1 GBM 2103.7 1168.8 80.0 648.4 230.5 181.22 GBM 1656.9 1073.5 54.3 342.0 184.6 85.23 GBM 2442.2 1147.5 112.8 844.8 277.4 204.54 GBM 844.9 425.8 98.4 235.2 76.7 206.75 GBM 1262.6 834.3 51.3 317.2 187.5 69.26 GBM 1943.8 892.9 117.7 896.0 218.5 310.17 GBM 1928.9 929.2 107.6 819.1 297.5 175.38 GBM 1750.9 824.0 112.5 662.2 167.5 295.49 GBM 2158.3 596.8 261.6 670.3 160.9 316.6

10 GBM 1543.9 726.8 112.4 434.8 161.2 169.711 GBM 1467.9 848.4 73.0 333.5 162.9 104.712 GBM 1559.6 857.5 81.9 611.4 251.9 142.713 GBM 1655.3 887.5 86.5 639.9 198.4 222.414 GBM 1573.2 841.8 86.9 196.7 123.1 59.715 GBM 1172.6 626.1 87.3 379.6 190.5 99.316 GBM 1758.4 862.2 103.9 355.0 173.7 104.4




normal gray/white matter with a varying degree of neuro-architectural destruction.33,36 The histological subtype of the tumors also affects the characteristics of this region. Invasive tumors infiltrating this region result in a low ADC value, while noninvasive tumors causing vasogenic brain edema result in a higher ADC value than in CNWM.23 In our study, the ADC values of Definite-NePDHL, when compared with that of CNWM, were lower in all but 4 cases. Such low ADC values for Definite-NePDHL with characteristic nonenhancement suggest increased cellu-larity resulting from the infiltration by glioma cells with subsequent cellular compression and decreased free ex-tracellular space. The resulting relative tumor ischemia due to insufficient vascular proliferation and neovascular-ity explains why Definite-NePDHL precedes abnormal enhancement and BBB disruption.11,16,23 In those 4 cases,

the higher ADC values may be explained by the ROIs that were placed in heterogeneous regions, which are subject to contamination by the surrounding tissue or significantly higher free water content due to vasogenic edema and/or destruction of tissue.33,36 Glioblastoma has a dismal prog-nosis, even with the latest multimodality treatment.22,28,30 Prognostic factors for glioblastoma have been extensively studied and include patient-related (age and preoperative KPS score), tumor-related (histology, location, size, grade, and necrosis), and treatment-related factors (extent of re-

TABLE 4. SIRs of Probable-NePDHL and CNWM on DWI

Sample No. Histological Diagnosis

b-1000 b-4000Signal Intensity on DWI

SIR Signal Intensity on DWI

SIR Probable-NePDHL CNWM Probable-NePDHL CNWM

1 Malignant lymphoma 1390.7 1159.2 20.0 505.3 365.2 38.42 Malignant lymphoma 1333.8 1259.9 5.9 300.7 267.3 12.53 Malignant lymphoma 1480.5 1298.8 14.0 259.1 217.4 19.24 Malignant lymphoma 1412.6 1243.2 13.6 418.1 365.2 14.55 Malignant lymphoma 1442.3 1241.3 16.2 320.2 221.7 44.56 Malignant lymphoma 1748.5 1445.4 21.0 696.9 467.9 48.97 Malignant lymphoma 1217.1 1053.0 15.5 331.0 295.5 11.9

TABLE 5. Mean ADC values (b = 1000) of Definite-NePDHL and CNWM in positive cases

Sample No.

Age (yrs) Sex

ADCMIN of CNWM*

ADCMIN of Definite-NePDHL*

1 68 M 1.11 0.6532 49 M 0.856 0.6913 65 M 0.889 0.584† 38 F 0.777 0.9785† 59 M 0.807 0.9316 64 M 0.833 0.5337 65 F 0.981 0.6028 70 M 0.827 0.859‡ 55 M NA NA

10 50 M 0.737 0.58711 73 M 1.02 0.65712 78 F 0.681 0.53313 65 M 0.853 0.6414† 61 F 0.852 1.0215 15 M 0.933 0.73316† 71 M 0.828 1.23

NA = not applicable. * ADC values are expressed as ×10−3 mm2/sec with b = 1000 sec/mm2.† Cases with ADC values for Definite-NePDHL that were higher than CNWM. ‡ Patient was excluded from the ADC analysis because the DW MR data were insufficient.

TABLE 6. Univariate and multivariate analyses of the prognostic factors for glioblastoma patients

Prognostic Factor

No. of

Patients

Median Overall

Survival (mos)

p Value*Univariate Analysis

Multivariate Analysis

Age <50 yrs 11 17.4 0.8131 0.7369 ≥50 yrs 53 19.5Sex M 37 18.2 0.4408 0.9741 F 27 20.5Symptom duration <3 mos 53 18.2 0.5354 0.8334 ≥3 mos 11 23.6KPS score ≥80 26 24.6 0.0028† 0.1148 ≤70 38 16.3Extent of surgery Total 24 24.3 0.0012† 0.0351† Nontotal‡ 40 14.5RPA class Classes 3–4 34 23.9 0.0006† 0.7407 Classes 5–6 30 14.0Definite-NePDHL Negative 48 21.8 0.0007† 0.0420† Positive 16 11.9

* p values were calculated using the log-rank test and Cox proportional hazards model.† p < 0.05.‡ Nontotal resection includes subtotal resection, partial resection, and biopsy.




section, radiation dose, and concurrent chemotherapy).9,32 The prognostic value of radiological features like the pres-ence of necrosis, calcification, tumor volume, and angio-graphic vascularity have been studied,4,23 but the predic-tive value of the radiological features of the peritumoral region has not been ascertained.

Our results showed that total surgical removal was a significant prognostic factor, concurrent with other stud-ies.4,22,28,30,32 The presence of Definite-NePDHL was a sig-nificant predictor of reduced survival in glioblastoma pa-tients. Unlike in previous studies,9,11 the recurrence of glio-blastoma at Definite-NePDHL could not be conclusively ascertained, as the natural history of tumor recurrence was likely disrupted due to the therapeutic postoperative

irradiation of the lesion in our patients. Furthermore, the presence of Definite-NePDHL was a significant indica-tor of early progression and early local recurrence as well as distant/dissemination recurrence in glioblastoma. Our results are consistent with previous studies that reported that the presence of diffusion restriction was associated with early local recurrence.9,11 The presence of Definite-NePDHL could predict the extent of resection obtainable in glioblastoma patients. Total resection was obtainable in 1 patient with Definite-NePDHL and nontotal resec-tion in the remaining 15 patients. This may be associated with the invasive and/or aggressive character of this tumor subgroup. Definite-NePDHL may be associated with DTI abnormality, and extensive resection including Definite-

FIG. 4. Kaplan-Meier survival curves illustrating the cumulative survival rates for patients with glioblastoma. A–C: Comparisons were made between patients with KPS score ≥ 80 and KPS score ≤ 70 (A), Definite-NePDHL (D-NePDHL)–positive and –nega-tive patients (B), and patients who underwent total and nontotal removal (C). D: Overall survival for glioblastoma stratified by RPA classification showing significant differences in overall survival between the RPA classes: Group 1 (Classes 3 and 4) versus Group 2 (Classes 5 and 6).

FIG. 5. Kaplan-Meier survival curves (log-rank test) showing that tumor progression (A) and distant/dissemination recurrence (B) occurred significantly earlier in patients positive for Definite-NePDHL than patients negative for Definite-NePDHL.




NePDHL may be associated with longer progression-free survival and overall survival as reported in a previous study.39 However, further studies are needed to confirm this association.

Our study has some limitations. The small sample size and lack of prospective studies in a large population limit the validity. Among glioblastoma differentials, our study included only malignant lymphoma and metastatic brain tumors. Grade III glioma, HIV-positive lymphoma, and lymphomatosis cerebri could also exhibit similar charac-teristics, which were not included. ADC calculation might be influenced by the setting of the ROI in heterogeneous tumors. Further studies are required to recommend the ex-act b-value for high–b-value DWI and is beyond the scope of this study. We are planning future prospective studies, including MR spectroscopy, DTI, and histological confir-mation of tumor invasion at Definite-NePDHL, to eluci-date its pathophysiological mechanism.

ConclusionsOur study introduces a diagnostic and differentiating

radiological feature for glioblastoma and proposes the usefulness of high–b-value DWI for tumor differentiation. Definite-NePDHL is present in about a quarter of glioblas-toma cases, and it is a highly specific finding and a signifi-cant indicator for early local recurrence as well as distant/dissemination recurrence and poor prognosis. We propose Definite-NePDHL as a novel diagnostic and specific poor prognostic indicator for glioblastoma. We also recommend

the routine use of high–b-value DWI for all brain MRI studies.

AcknowledgmentsThis study was partially supported by a Grant-in-Aid for Sci-

entific Research (C) from the Japan Society for the Promotion of Science (no. 16K10757).

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p Value*Negative (n = 48) Positive (n = 16)

Mean age, yrs 60.6 ± 14.6 59.1 ± 15.9 0.71Sex M 26 11 0.31 F 22 5KPS score ≥80 21 5 0.381 ≤70 27 11Symptom duration ≥3 mos 9 2 0.569 <3 mos 39 14RPA class ≥5 20 11 0.067 ≤4 28 5Mean ADCMIN

b-1000 0.907 ± 0.193 0.835 ± 0.171 0.197 b-4000 0.548 ± 0.091 0.524 ± 0.094 0.375IDH-1 mutation Negative 42 15 0.467 Positive 6 1

Values are shown as the number of patients or mean ± SD.* Logistic regression analysis.




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DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

Author ContributionsConception and design: Kolakshyapati, Yamasaki. Acquisition of data: Kolakshyapati, Karlowee, Takayasu, Nosaka, Amatya, Takeshima, Akiyama, Sugiyama, Yamasaki. Analysis and inter-pretation of data: Kolakshyapati, Karlowee, Yamasaki. Drafting the article: Kolakshyapati. Critically revising the article: Kolak-shyapati, Adhikari, Yamasaki. Reviewed submitted version of manuscript: all authors. Approved the final version of the manu-script on behalf of all authors: Kolakshyapati. Statistical analysis: Kolakshyapati, Yamasaki. Administrative/technical/material sup-port: Kurisu. Study supervision: Kurisu, Yamasaki.

CorrespondenceFumiyuki Yamasaki, Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. email: [email protected].


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