Quantitative Imaging Analysis of FDG PET/CT Imaging for Detection of Central Neurolymphomatosis in a Case of Recurrent Diffuse B-Cell Lymphoma

Abstract

Neurolymphomatosis (NL) is a rare disease characterized by malignant lymphocytes infiltrating various structures of the nervous system. It typically manifests as a neuropathy involving the peripheral nerves, nerve roots, plexuses, or cranial nerves. It often presents as a complication of lymphoma, but it can be the presenting feature of recurrent lymphoma. It is essential to identify and initiate treatment early with chemotherapy and/or radiation therapy in all cases of nodal or visceral (including neural) involvement with lymphoma. There are various diagnostic tests that can be used for its detection, such as cerebrospinal spinal fluid (CSF) cytology, electromyography (EMG), magnetic resonance imaging (MRI), and positron-emission tomography/computed tomography (PET/CT). FDG-PET/CT is the standard of care in lymphoma staging, restaging, and therapy response assessment, but has an inherent limitation in the detection of disease involvement in the central nervous system. While that is mostly true for visual assessment, there are quantitative methods to measure variation in the metabolic activity in the brain, which in turn helps detect the occurrence of neurolymphomatosis.

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Received 10/26/2015
Review began 10/28/2015
Review ended 11/03/2015
Published 11/13/2015
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Quantitative Imaging Analysis of FDG
PET/CT Imaging for Detection of Central
Neurolymphomatosis in a Case of Recurrent
Diffuse B-Cell Lymphoma.
Faiq Shaikh , Derek Savells , Omer Awan , Faisal Inayat , Ammar Chaudhry , Nivedita
Jerath , Michael M. Graham
1. Imaging Informatics, University of Pittsburgh Medical Center 2. Molecular Imaging Physician, S&L
Readings, LLC. 3. Department of Radiology, University of Iowa Hospitals and Clinics 4. Department of
Radiology, Dartmouth Hitchcock Medical Center 5. Department of Medicine, New York-Presbyterian
Hospital, Weill Cornell Medical College, New York, N.Y., USA 6. Neuroradiology, Johns Hopkins
University School of Medicine 7. Department of Neurosurgery, University of Iowa Hospitals and Clinics
 Corresponding author: Faiq Shaikh, faiq.shaikh@hotmail.com
Disclosures can be found in Additional Information at the end of the article
Abstract
Neurolymphomatosis (NL) is a rare disease characterized by malignant lymphocytes infiltrating
various structures of the nervous system. It typically manifests as a neuropathy involving the
peripheral nerves, nerve roots, plexuses, or cranial nerves. It often presents as a complication of
lymphoma, but it can be the presenting feature of recurrent lymphoma. It is essential to
identify and initiate treatment early with chemotherapy and/or radiation therapy in all cases of
nodal or visceral (including neural) involvement with lymphoma. There are various diagnostic
tests that can be used for its detection, such as cerebrospinal spinal fluid (CSF) cytology,
electromyography (EMG), magnetic resonance imaging (MRI), and positron-emission
tomography/computed tomography (PET/CT). FDG-PET/CT is the standard of care in
lymphoma staging, restaging, and therapy response assessment, but has an inherent limitation
in the detection of disease involvement in the central nervous system. While that is mostly true
for visual assessment, there are quantitative methods to measure variation in the metabolic
activity in the brain, which in turn helps detect the occurrence of neurolymphomatosis.
Categories: Neurology, Oncology, Radiology
Keywords: neurolymphomatosis, fdg pet/ct, pneuro, diffuse large b-cell lymphoma (dlbcl),
quantitative, analysis
Introduction
We present a case where neural involvement with diffuse large B-cell lymphoma (DLBCL) was
suspected clinically in a patient otherwise thought to be in remission. Based on the concern
raised by MRI findings, an FDG PET/CT scan was performed, which revealed abnormal
metabolic activity in the brain on quantitative image analysis using the PMOD-PNeuroR tool
(PMOD Technologies, Zurich, Switzerland).
Case Presentation
Signed informed patient consent was obtained for this patient's care.
1 2 3 4 5 6
7 3
Open Access Case
Report DOI: 10.7759/cureus.379
How to cite this article
Shaikh F, Savells D, Awan O, et al. (November 13, 2015) Quantitative Imaging Analysis of FDG PET/CT
Imaging for Detection of Central Neurolymphomatosis in a Case of Recurrent Diffuse B-Cell Lymphoma..
Cureus 7(11): e379. DOI 10.7759/cureus.379

We present a case of a 48-year-old female with an existing diagnosis of Stage IV diffuse large B-
cell lymphoma (DLBCL), in remission as per a surveillance 18F-fluorodeoxyglucose positron
emission tomography/computed tomography (FDG-PET/CT) scan, who presented with left arm
weakness after a fall. The initial magnetic resonance imaging (MRI) revealed enhancement in
two upper cervical roots (Figure 1).
FIGURE 1: Initial MRI on presentation
Left to right
-
1st image:
Axial T1-weighted fat-sat post-contrast image shows asymmetric
enlargement and uniform enhancement of the left C4-5 nerve root (yellow arrow).
2nd image:
Corresponding coronal T2-weighted image showing the lesional enhancement (red arrow).
3rd
image -
The nerve root shows intense diffusion restriction of diffusion weighted imaging (blue
arrow).
Electromyographic (EMG) studies demonstrated good sensory potentials, but fibrillations were
noted in the muscles innervated by C5-6. Thus, the working diagnosis was cervical
plexitis/radiculitis, and treatment with Neurobion (vitamin supplements) was initiated.
However, the patient’s symptoms continued to worsen in the ensuing month with the new
development of right shoulder pain. A repeat cervical spine MRI was performed, which revealed
an enhancing mass along the left C5 nerve root suggestive of a neurogenic tumor. A lumbar
puncture was then performed and cytology of the cerebrospinal fluid (CSF) revealed
lymphocytosis without evidence of tumor cells. Neurosurgery was consulted, and a
laminectomy was performed, along with the excision of the cervical root mass, the pathology of
which revealed DLBCL. This prompted an MRI of the brain, and it demonstrated periventricular
and callosal hyperintense foci with faint enhancement and diffusion-weighted hyperintensity
(Figure 2), which were felt to be concerning for lymphoma. A repeated LP showed the presence
of lymphoma cells. The bone marrow biopsy was negative for malignancy.
2015 Shaikh et al. Cureus 7(11): e379. DOI 10.7759/cureus.379 2 of 8

FIGURE 2: Comparison of initial and follow-up MR images
Images from the initial
(top row)
and subsequent MRI
(bottom row)
demonstrating an additional
site of lymphomatous involvement. Abnormal flair intensity
(1st column)
and abnormal patchy
enhancement is seen on post-contrast images in the periventricular white matter and corpus
callosum
(second column)
with corresponding DWI restriction
(third column).
Based on this clinical picture and the suggestive findings on MRI, an FDG-PET/CT was
performed. However, there were no visually apparent hypermetabolic lesions on initial
assessment. However, acknowledging the fact that FDG physiologically accumulates in the
brain tissue and an otherwise hypermetabolic lesion could be obscured, brain metabolic activity
was further assessed using the PMOD/PNeuroR software application (Figure
3). PMOD/PNeuroR software is a quantitative image analysis tool that performs quantification
of variations in the FDG activity (on PET/CT) in different regions of the brain (based on MRI
parcellation), which are expressed on a color spectrum as standard deviations from the normal
PET database. The application of this tool revealed an abnormally increased heterogeneous
pattern of tracer uptake in various regions of the brain (Table 1), which was suggestive of
disease involvement. Areas, such as the thalami, demonstrated correlative abnormal findings
on MRI and the quantitative PET assessment. The patient was started on hyper-CVAD
(cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and intrathecal
methotrexate with an ara-C regimen.
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FIGURE 3: Comparison of initial and follow-up PET/CT images
using PMOD/PNeuro tool
The initial PET/CT demonstrates no areas of abnormal uptake to suggest brain involvement
(top row).
The subsequent PET/CT demonstrates patchy areas of intensely increased uptake
(middle row)
. Subtraction images show difference increase in uptake suggestive of
lymphomatous infiltration
(third row).
The analysis performed suggested a heterogeneous
pattern of uptake in the cortical gray matter and callosal white matter, and many areas
corresponded to abnormalities detected by MRI.
2015 Shaikh et al. Cureus 7(11): e379. DOI 10.7759/cureus.379 4 of 8

Brain Region (Select) Difference SUVbw (g/m) % Difference
Hippocampus, right 0.15724489 17.9
Hippocampus, left 0.18969916 22.0
Amygdala, right 0.16699445 20.6
Amygdala, left 0.19704809 24.1
Parahippocampus, right 0.16610518 20.7
Parahippocampus, left 0.19538376 24.5
Nucleus accumbens, right 0.30946808 28.6
Nucleus accumbens, left 0.30160365 26.2
Caudate nucleus, right 0.15631517 17.4
Caudate nucleus, left 0.12730549 14.3
Thalamus, right 0.2861532 36.4
Thalamus, left 0.18329167 19.0
Substantia nigra, right 0.21899194 25.8
Substantia nigra, left 0.21431143 23.7
TABLE 1: Data from the quantitative image analysis of differential metabolic activity
using PNeuro
The select areas of the brain demonstrating greatest positive differential uptake included hippocampal and parahippocampal
regions, as well as thalamic and basal nuclei.
(SUVbw = Standardized Uptake Value - using body weight).
Discussion
Neurolymphomatosis is a rare manifestation of hematologic malignancies characterized by an
infiltration of the cranial nerves, peripheral nerves, nerve roots, or nerve plexuses by malignant
lymphocytes [1]. It causes progressive and painful axonal polyneuropathy and may occur as the
initial manifestation, complication, or the relapsing feature of non-Hodgkins lymphoma (NHL).
Leptomeningeal involvement is seen in at least half of the reported cases [2]. Approximately
80% of the reported neurolymphomatosis (NL) cases originate from B-cells, most of which
represent aggressive disease [3]. Involvement of the nervous system by NHL is seen in
approximately 10-25% of the cases [3-5].
Given the heterogeneous pattern of its involvement in the central nervous system and the
limited methods available to detect brain tissue involvement, NL may be exceptionally difficult
to diagnose. FDG PET/CT is routinely performed as the modality of choice for staging,
restaging, therapy response, and remission assessment of NHL [6]. It is highly useful in the
2015 Shaikh et al. Cureus 7(11): e379. DOI 10.7759/cureus.379 5 of 8

detection of clonal mutation that renders the indolent variants of disease to be more
aggressive, warranting a change in management [7]. However, FDG PET/CT is limited in the
evaluation of hypermetabolic disease involvement in the central nervous system, owing to the
brain's avid glucose dependence, resulting in intensely increased uptake of FDG [8]. This results
in a high tumor-to-background ratio within the brain and obscures the detection of
hypermetabolic foci of disease involvement therein, especially if it is patchy in distribution.
MRI, on the other hand, can suggest a lymphomatous involvement of the CNS fairly well, as
suggested by hypointense signal intensity on T1-weighted and iso- to hyperintense signal on
T2-weighted images, and intense homogeneous gadolinium enhancement and restricted
diffusion [9].
In our patient, the MRI demonstrated periventricular and callosal hyperintense foci with faint
enhancement and diffusion restriction, which were concerning for foci of neural recurrence of
DLBCL. While the PET/CT was performed to evaluate the extent of recurrence elsewhere in the
body, special attention was paid to the PET imaging features of the nervous system based on
the concerns raised by the preceding MRI features. Conventionally, visual assessment of the
brain (on axial slices) and the spinal cord (on sagittal slices) on PET/CT provides an overview of
the general biodistribution of FDG in the central nervous system [10]. Subtle changes are
considered nonspecific and only major differences in tracer distribution are generally reported,
such as those secondary to cerebrovascular stroke with penumbra or encephalomalacia [11].
This is primary due to the fact that the neurons utilize glucose for their energy needs
independent of insulin requirement, which renders them FDG-avid irrespective of the
postprandial/fasting state [12]. While the peripheral nervous system follows the same
physiologic principles, the signal count is too low for physiologic or pathologic activity to be
demonstrated by cranial or peripheral nerves on PET imaging; however, a number of cases with
intensely FDG-avid peripheral neurolymphomatosis have been reported [13].
In this case, as prompted by the abnormal MRI findings suggestive of lymphomatous
infiltration, the decision was made to perform a quantitative assessment of the metabolic
activity in the brain using a software application called PMOD (PNEURO). Quantitative
assessment of the metabolic activity as a measure of malignant infiltration using various
software applications is commonplace in cancer imaging [14]. PMOD/PNEURO creates an
activity map of the patient’s brain through MRI parcellation for anatomic correlation, and the
patterns of activity are depicted as a number of standard deviations from the mean activity in a
particular region based on a normal PET database [15]. The analysis performed in this case
suggested a heterogeneous pattern of uptake in the cortical gray matter and callosal white
matter and was highly suggestive of disease involvement. While there were a number of brain
regions with concurrent abnormal findings on both MRI and PET scans, some variations were
observed between the two modalities, which may be attributable to the difference in their
sensitivities and detection methods and to the variations in the metabolic and anatomic
manifestations of the disease.
Histopathologic correlation, while being the gold standard for diagnosis, is difficult to obtain
with CNS lesions [16]; this case demonstrates the use of quantitative functional image analysis
as an adjunct to anatomic imaging in order to provide reasonable confidence in the diagnosis of
NL, especially when a biopsy is precluded. Through this example. we highlight the
methodological pitfall of PET-CT when it comes to reader’s reliance on visual assessment of
certain regions, such as the central nervous system, which is perhaps more expedient but can
potentially overlook subtle variation in FDG uptake patterns and provides the example of the
use of visual assessment as a viable and superior alternative.
Conclusions
Utilizing analytical tools for quantitative assessment of PET imaging features, such as
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PMOD/PNEUROR, should be considered for accurate detection when infiltrative disease
involvement is suspected in organs that show high background FDG activity as is the case with
the central nervous system. Innovative tools such as these are becoming increasingly
commonplace and many of them are getting approval for clinical use, their judicious use can
improve the diagnostic accuracy of disease processes.
Appendices
PNeuro and PMOD are registered trademarks of PMOD Technologies, Zurich, Switzerland.
Additional Information
Disclosures
Human subjects: Consent was obtained by all participants in this study.
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