Primary Central Nervous System Lymphoma Mimicking Longitudinally Extensive Transverse Myelitis

Abstract

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extra-nodal non-Hodgkin’s lymphoma. Three regions can be involved in PCNSL: the brain, the spine, or the vitreus and retina. Spinal PCNSL is rare. It can mimic neoplasm, infection, and inflammation. Diagnostic confirmation is by tissue biopsy, and even then, tissue corroboration may be altered by an inflammatory overlay. We report a 59-year-old woman who we saw after she had 4 weeks of ascending tetraparesis plus bowel and bladder incontinence. Upon presentation, the patient was ventilator-dependent and locked-in. She reported normal sensation through eye-blinking. Magnetic resonance imaging (MRI) brain revealed signal intensity in the bilateral corona radiata and restricted diffusion in the right thalamus, whereas, MRI cervical, and thoracic spine showed T2 prolongation in the anterior medulla and upper cervical cord, with enhancement to C2-C3, and long segment hyperintensity from T1-T9 levels, respectively, suggestive of neuromyelitis optica spectrum disorder. Cerebrospinal fluid cytomorphology and flow cytometry were inconclusive for lymphoma/leukemia, but oligoclonal bands were present. Serum aquaporin-4 (AQP-4) antibodies were negative. MR spectroscopy demonstrated NAA reduction, mild lipid lactate peak, and relative reduction of choline on the side of the lesion, favoring demyelination. She received 5-days of intravenous methylprednisolone, followed by 7 sessions of plasma exchange without clinical improvement. Stereotactic biopsy of the right thalamic lesion revealed diffuse large B-cell lymphoma. PCNSL can mimic a demyelinating process early on, as steroid treatment could disrupt B-cell lymphoma cells, thus masking the correct diagnosis.

Introduction

Locked-in syndrome is a rare entity characterized by anarthria, tetraplegia with preserved consciousness, and vertical eye movements (which may aid in non-verbal interaction). Common causes include infarction, hemorrhage, or traumatic insult to the basis pontis while brain stem encephalitis, meningitis, demyelination (central pontine myelinolysis, multiple sclerosis, Guillain-Barre syndrome) and malignancy are less common causes.^1,2

Primary Central Nervous System Lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL), accounting for 1-3% of all NHL, and most commonly arising from a B-cell lineage. It can involve the eyes, leptomeninges, brain parenchyma, and rarely spinal cord without evidence of systemic disease.³ It is a difficult diagnosis to make due to the heterogeneity of clinical symptoms which can vary from focal neurological deficits, headache, cognitive decline, nausea, and vomiting. Radiologically, lesions enhancing in the corpus callosum, basal ganglia, and periventricular white matter are common, while brainstem, cerebellum and spinal cord are less frequent.³

Historically, PCNSL has been a mimicker of metastases, high-grade gliomas (HGG), granulomatous, infectious, and demyelinating diseases like multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) or acute disseminated encephalomyelitis.^3,4 Definitive confirmation is by tissue biopsy, and even then, tissue corroboration may be altered by the inflammatory overlay or by steroid use.⁵

In this report, we present a case of diffuse large B-cell lymphoma that presented as a locked-in syndrome with imaging convincingly mimicking longitudinally extensive transverse myelitis (LETM).

Case Description

A 59-year-old woman was transferred from an outside hospital for new-onset ascending weakness. She developed progressive tetraparesis and bowel and bladder incontinence over a week. She underwent thoracic discectomy for a T5-6 vertebral disc bulge 3 weeks before presenting to us due to bilateral leg weakness. After the procedure, she was successfully undergoing inpatient rehabilitation for a week, when she started having progressive weakness in her legs. Thoracic spine imaging at the outside hospital reportedly showed postoperative edema. She was treated with a 3-day course of intravenous (IV) high dose (1 mg/kg) methylprednisolone before being transferred to our tertiary care center.

Upon presentation, the patient was ventilator dependent (intubated at the transferring hospital 3 weeks s/p thoracic discectomy), nauseated with frequent hiccups, alert, and awake. Pupils were equal and reactive with intact vertical and horizontal eye movements. Power in all extremities was 0/5 on the Medical Research Council scale, but she reported normal sensation through eye-blinking. Deep tendon reflexes were 3+ with upgoing plantar responses bilaterally. The exam was consistent with incomplete locked-in syndrome (LiS).

Magnetic resonance imaging (MRI) of the brain was notable for restricted diffusion in the right thalamus and corona radiata [Figure 1 A, B], increased T2 and Fluid-attenuated inversion recovery (FLAIR) signal in the periventricular and deep white matter perpendicular to callososeptal interface along with the anterior aspect of the medulla extending into the cervical spinal cord up to C2-C3 level [Figure 1 C, D] which was favored to be secondary to demyelination, specifically NMOSD. Therefore, the patient was started on a 5-day course of IV high dose methylprednisolone (1 mg/kg).

Figure 1.

Brain, cervical spine magnetic resonance imaging (MRI) at initial presentation. A, Diffusion-weighted imaging axial image with hyperintensity of right corona radiata lesion. B, Apparent diffusion coefficient axial image with the corresponding hypointensity of right corona radiata lesion. C, T2-weighted axial image showing hyperintensity in the medulla. D, T2-weighted sagittal image of the cervical spine with increased signal extending up to the C2-C3 level.

Initial cerebrospinal fluid (CSF) studies were significant for 5 CSF specific oligoclonal bands and an elevated IgG index. HIV and hepatitis antibodies were not detected. The NMOSD and lymphoma/leukemia workup were inconclusive based on blood and CSF studies including negative AQP-4 antibodies. As there was no clinical improvement status post methylprednisolone, the patient underwent 7 cycles of plasmapheresis. Repeat MRI of the brain, cervical spine redemonstrated the previously described lesions but with increasing size and edema [Figure 2 A-C]. MRI thoracic spine showed a long segment signal from the T1-T9 level with patchy enhancement suggestive of LETM [Figure 2 D], making for a diagnosis of NMOSD without aquaporin-4 (AQP-4) seropositivity. Magnetic resonance spectroscopy demonstrated NAA reduction, mild lipid lactate peak, and relative reduction of choline in the right thalamic lesion [Figure 2E], favoring a demyelinating process.

Figure 2.

Brain, cervical, thoracic spine magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and tissue biopsy of the right corona radiata lesion at the 3-week from admission. A, Diffusion-weighted imaging axial image with worsening of the right corona radiata lesion with midline shift. B, T2-weighted axial image showing hyperintensity in the medulla. C, T1-weighted sagittal image of the cervical spine with contrast enhancement up to the C2-C3 level. D, T2-weighted sagittal image of the thoracic spine with long segment hyperintensity from T1-T9 levels. E, MRS showing NAA reduction, mild lipid lactate peak, and relative reduction of choline in the right thalamic lesion. F, Tissue biopsy showing large lymphomatous cells showing irregular nuclear membrane and prominent nucleoli.

Due to the lesions progressing on repeat imaging and the lack of clinical improvement, stereotactic needle biopsy of the right thalamic lesion was pursued which showed perivascular large lymphoid cells with eosinophilic bodies [Figure 2 F]. Beta-2 microglobulin was 4 (reference range 0.80-2.20 mg/L); LDH: 153 (reference range 135-214 U/L). Serum LDL was 48 mg/dl (Optimal <100 mg/dl), Total Cholesterol 97 mg/dl (desirable <200 mg/dl), Triglycerides 113 mg/dl (normal <150 mg/dl). Immunohistochemical staining and flow cytometric analysis was positive for CD-20, BCL-6, MUM-1, and negative for CD-10 and Cyclin-D1. Fluorescent in situ hybridization for BCL-2, BCL-6, and MYC rearrangements were negative. All these findings were consistent with a large B-cell lymphoma with no evidence of double- or triple-hit lymphoma. Repeat CSF cytomorphology and flow cytometry showed the same findings.

Hematology was consulted for the staging of the lymphoma, and the patient was diagnosed as PCNSL based on normocellular bone marrow and unremarkable systemic imaging. Due to poor response to 2 cycles of high dose methotrexate chemotherapy, family decided to pursue with home hospice.

Discussion

Primary central nervous system lymphoma constitutes less than 1% of all brain tumors, with diffuse large B-cell lymphoma being the most common. PCNSL has been traditionally described in immunocompromised patients, but of late, the incidence has been rising among immunocompetent patients > 65 years old.⁶ Depending on the site of CNS involvement, patients with PCNSL manifest with focal neurological deficits, seizures, headaches, nausea, vomiting, papilledema, and cognitive deficits over weeks.⁷ Our patient started with bilateral lower extremity weakness that progressed to locked-in syndrome over 4 weeks.

The term “locked-in” first coined by Plum and Posner to describe the state of tetraplegia and anarthria with preserved consciousness.² LiS characteristically affects corticospinal (tetraplegia) and corticobulbar tracts (speech and vocalization issues); but with sparing of spinothalamic tracts (intact sensation) and midbrain tectum (vertical eye movements, blinking).⁸ Locked-in syndrome can be classified into 3 types: classic, incomplete, and total. Classic LiS has complete immobility with preserved blinking, vertical eye movements, and awareness, whereas incomplete LiS entails additional voluntary movements in the fingers or neck besides the blinking and eye movements. Total LiS as the name suggests complete immobility including eye movements.⁹ Our patient manifested with features of incomplete LiS with absolute tetraplegia.

Radiologically, PCNSL being a hypercellular lesion, appears hyperdense on computed tomography (CT), iso-hypointense on T2-weighted sequence, restricted diffusion and homogenous enhancement on MRI with vasogenic edema and mass effect.¹⁰ The contrast enhancement is due to the characteristic perivascular accumulation of lymphoma cells disrupting the blood-brain barrier.⁶ It commonly occurs as a supratentorial single lesion with a predilection for periventricular white matter, corpus callosum, and basal ganglia on MRI.³ Infrequently, it can be multifocal and extend to the contralateral hemisphere mimicking glioblastoma; it can involve multiple regions (brainstem, cerebellum, pituitary, hypothalamus, and spinal cord) mimicking demyelination (MS, NMOSD).^4,6 Our patient demonstrated homogenously enhancing lesions both supra-(thalamus) and infratentorial (rostral medulla, cervicomedullary junction, cervical and thoracic spine) which fit the criteria for NMOSD without AQP-4 IgG.¹¹

Ancillary testing of PCNSL with magnetic resonance spectroscopy (MRS), CSF examination, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan can aid in the diagnosis of PCNSL. MRS in PCNSL shows reduced N-acetyl aspartate (neuronal damage), elevated lipid (lymphocyte-mediated fatty moieties release), lactate (anaerobic metabolism) peaks, and elevated choline to creatine ratio (elevated membrane turnover).¹¹ Differentiating PCNSL from glioblastoma based on the level of lipid peak has been well described, but differentiating from demyelinating disorders like MS, NMOSD is still a gray zone due to overlap of metabolic abnormalities.^4,12 MRS findings can lead the clinician astray. This case helps illustrate that special care and caution must be used when interpreting these non-specific MRS findings.

CSF examination with flow cytometry (FC) and cytomorphology (CM) can detect lymphoma cells in about 1 in every 4 cases of PCNSL, while the presence of lymphocytic pleocytosis and oligoclonal bands is nonspecific and may not aid in a definitive diagnosis.^3,13 The role for CSF biomarkers of B-cell proliferation is an upcoming field with recent data demonstrating an increase in CSF IL-10, CXCL-13 as a reliable diagnostic biomarker for large B-cell PCNSL.⁶

18F-FDG-PET scan would show an increased homogeneous signal, often in the subcortical lesions with relative hypometabolism in the adjacent cortex due to perilesional edema.³

The definitive diagnosis of PCNSL is through a stereotactic brain biopsy especially when ancillary testing through imaging, CSF FC, CM are inconclusive. Most PCNSLs as discussed earlier are diffuse large B-cell lymphoma (DLBCL; 95%) and rarely T-cell, Burkitt, marginal zone, or lymphoblastic lymphoma.^6,7 Histologically, inflammatory “sentinel” demyelination may precede PCNSL especially when the biopsy has been obtained after steroid administration which alters B-lymphoma cells through apoptosis, thereby leaving a robust T-cell mediated immune response against the lymphoma.^14,15 It is thus possible for PCNSL to be histologically misinterpreted as a result of inflammation and result in false-negative studies delaying definitive diagnosis. Management can include high-dose methotrexate-based chemotherapy and/or radiotherapy. Our patient had a laminectomy for suspected compressive myelopathy. A key learning point for this case is that disc bulges are common. When the extent of spinal cord signal change is out of proportion to the degree of cord compression, and there is no pancake enhancement, then alternate diagnoses should be considered, and surgery should not be offered. Other differential diagnosis especially with acute myelopathy features include neuromyelitis optica, neurosarcoidosis, transverse myelitis, arbovirus infection, metastatic disease. However, the work up did not suggest any these conditions.

In summary, our patient was misdiagnosed appropriately as having NMOSD as she fulfilled the 2015 criteria for NMOSD without AQP-4 IgG, both clinically and radiologically, and was started on high dose methylprednisolone and several cycles of plasmapheresis. Due to a lack of clinical improvement and lesions progressing on neuroimaging despite being on acute immunosuppressive therapies, a stereotactic brain biopsy was obtained which showed findings suggestive of PCNSL (specifically diffuse large B-cell lymphoma). This case exemplifies that PCNSL can cause spine diseases that mimic LETM with accompanying CSF-specific oligoclonal bands. When a patient with suspected NMOSD does not respond to usual therapies, alternative diagnoses need to be considered.