Lymphomatous Meningitis as a Presentation of Non-Hodgkin Lymphoma

Marc C. Chamberlain, MD

Cauda Equina Lymphoma: A Case Report Including Postmortem Examination

Aditya Mandawat, BS1
M. Chadi Alraies, MD2
Kennon Miller, MD3
Sarah Ondrejka, MD3
Stephen Smith, MD4


1School of Medicine, Case Western Reserve University; 2Departments of Medicine, 3Anatomic and Clinical Pathology, and 4Hematologic Oncologic and Blood Disorders; Cleveland Clinic Foundation, Cleveland, Ohio 

Address correspondence to: Stephen D. Smith, MD, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Foundation, R35, 9500 Euclid Avenue, Cleveland, OH 44195; Phone: 216-444-8258; Fax: 312-503-2555; E-mail:


While primary central nervous system (CNS) lympho-mas are rare, aggressive B-cell lymphomas may second-arily involve the CNS in up to 25% of patients with risk factors, particularly multiple extranodal sites of dis-ease.1,2 B-cell lymphomas very rarely present solely with lumbosacral neurologic signs consistent with cauda equina syndrome. Detection of lymphoma with CNS involvement can be difficult, in spite of advances in cerebrospinal fluid (CSF) analysis and imaging techniques. Herein, we describe a case of fatal large B-cell lymphoma presenting with cauda equina syndrome, without discernible nodal disease but with diffuse extranodal involvement at autopsy. We review radiographic and pathologic features of cauda equina lymphomas in light of 19 cases reported in the last 2 decades.3-21

Case Presentation

A previously healthy 59-year-old man developed low back pain, symptoms of lumbar radiculopathy, and peroneal numbness following a cross-country drive. Contrast-enhanced magnetic resonance imaging (MRI) showed only mild lumbar spinal stenosis; electromyograms and nerve conduction studies were also unremarkable. Over 3 months, his symptoms progressed to paraplegia and urinary and fecal incontinence. Repeat contrast-enhanced MRI showed no interval change, and computed tomography (CT) of the chest, abdomen, and pelvis—and laboratory studies—were unremarkable.

At an academic center, laboratory evaluation found an elevated sedimentation rate and antinuclear antibody (titer 1:2500), and positive anticardiolipin antibody (IgM). Sural nerve biopsy was negative for vasculitis, and muscle biopsy showed denervation atrophy. Bone marrow biopsy, including flow cytometry, was negative. A diagnosis of antiphospholipid syndrome with myelitis was made, and therapy with hydroxychloroquine and high-dose steroids was started, with significant improvement.

However, upon tapering of the steroid dose, lower extremity weakness recurred. Steroids were resumed and cyclophosphamide was added. One week later, the patient developed renal failure (serum creatinine 3.4 mg/dL)
attributed to hyperglycemia with volume depletion related to steroids. The patient was transferred to our hospital for further management.

On admission, the patient was alert and oriented; no adenopathy was present on exam. Extremities were edematous. Motor strength and sensation to pinprick were decreased in the lower extremities. Lumbar puncture showed mildly elevated protein content, and CSF analysis showed rare atypical lymphocytes, though cytopathology review noted no malignancy. Flow cytometry was negative for a monoclonal B-cell population. Due to renal failure (creatinine clearance 20 cc/min), a noncontrast MRI of the brain and spine was performed; this showed findings consistent with arachnoiditis at L3–L4. CT imaging of the chest, abdomen, and pelvis was normal. Lactate dehydrogenase was mildly elevated (300 U/L; normal ≤220 U/L). Renal ultrasound showed kidney sizes of 12.9 and 13.0 cm. Steroids were decreased, and the patient clinically worsened, with diffuse loss of muscle strength. Due to worsening renal failure, the patient was started on hemodialysis; renal biopsy was not performed. A second bone marrow biopsy was undertaken. Soon after, the patient developed hypotension and was transferred to the intensive care unit; this was followed by respiratory failure, requiring intubation, and full cardiopulmonary arrest. Resuscitation efforts were unsuccessful. Bone marrow biopsy reported during this episode showed involvement by a CD20-positive large B-cell lymphoma representing less than 10% of marrow cellularity.

A postmortem exam was performed, revealing multiple segmental artery thrombi in both lungs. The cauda equina and nerve roots were thickened, and histologic examination showed an infiltrate of large, CD20-positive lymphocytes (Figure 1, normal cauda equina shown for comparison). The kidneys were pale in color and enlarged, with a combined weight of 784 grams (Figure 2, normal kidney shown for comparison). Both kidneys were involved by a diffuse lymphomatous infiltrate on microscopic examination (Figure 3). The lymphoma was also found to grossly involve the stomach, liver, pancreas, spleen, right coronary artery periadipose tissue, and adrenals. Microscopic involvement of the myocardium was also found on routine examination. Further pathology showed that the neoplastic B cells were CD20-positive, CD10-negative, Bcl6-positive, and MUM-1-negative, a germinal center phenotype large B-cell lymphoma based on criteria of Hans and colleagues.22

Discussion and Literature Review

Diffuse large B-cell lymphoma may present primarily with extranodal involvement in up to one-third of patients, with the gastrointestinal tract most frequently involved.23 However, presentation with cauda equina lymphoma is rare. We identified 19 English-language case reports of B-cell lymphomas presenting with cauda equina syndrome published since 1990; they are summarized in Table 1. Histologically, most cases are large B-cell non-Hodgkin lymphomas, though 2 reported cases of Hodgkin lymphoma, and a large proportion of cases of intravascular lymphoma (IVL, 6/19) were identified. Two of the cases of IVL were diagnosed on autopsy; others were diagnosed by muscle biopsy (2 cases), skin biopsy (1 case), or renal biopsy (1 case). In our case, large B-cell lymphoma with a germinal center phenotype was diagnosed on a second bone marrow biopsy immediately prior to expiration from pulmonary embolism and during postmortem examination. BCL-6 positivity in this case is consistent with an extensive prior report of extranodal lymphomas.23

Radiographic findings in cauda equina lymphoma may be subtle. The MRI finding of contrast enhancement (+/- thickening) of the cauda equina was the only abnormality in 6 of 9 reported cases. Other cases presented with mass lesions, bony disease, or distant adenopathy/organomegaly. Patients such as ours with a glomerular filtration rate of less than 30 mL/min/1.73 m2 constitute a particularly high-risk group for developing nephrogenic systemic fibrosis after gadolinium contrast for MRI, characterized by fibrosis of skeletal muscle, bone, lungs, pleura, and myocardium.24,25 Contrast nephropathy due to iodinated CT contrast may result in irreversible renal injury, necessitating lifelong dialysis.26,27 Furthermore, even when indicated in patients with normal renal function, contrast-enhanced MRI and CT may not detect lesions until late in the disease course. Clinical manifestations may precede MRI enhancement, particularly in lymphomas arising as primary tumors of the spinal cord, but they are often nonspecific.28 Contrast-enhanced MRI is also poor at detecting leptomeningeal dissemination, with enhancement detected in only 4% of patients versus 16.1% by cytology in a recent study.29 Use of positron-emission tomography (PET) has not been reported, though in absence of clear MRI or CT, abnormalities amenable to biopsy may have little potential to change management.

Finally, CSF analysis fails to provide a specific diagnosis in most cases. Elevated protein (12/19 reported cases) and pleocytosis (5/19) are common but nonspecific findings in published cases of cauda equina lymphoma. CSF cytology was positive in only 3 cases. Frequent false-negative results of CSF cytology in CNS lymphomas may be related to the paucity of tumor cells, which may in part be overcome by obtaining large CSF sample volumes and repeated sampling. Some data suggest steroids may not affect the chances of obtaining positive cytomorphology.29 Patients with suspected meningeal involvement by lymphoma should undergo evaluation by flow cytometry. In a study of 51 newly diagnosed aggressive B-cell lymphomas at risk for CNS involvement, all 11 cases of occult CSF involvement were detected by flow cytometry but only 1 by cytology (P=.002).30 Immunoglobulin heavy chain polymerase chain reaction (PCR) analysis is often discordant with CSF cytology (Kappa=0.18) and MRI (Kappa=0.19), and may be unreliable in patients taking corticosteroids.29,31 This may, nevertheless, be a useful test early in the diagnostic process.32 At present, a full diagnostic evaluation of CSF should include cytology and flow cytometry, and heavy-chain PCR in centers with the available technology and expertise.

In this case, diagnostic difficulties were posed by comorbidities (renal failure, discovered at the time of autopsy to be attributable to renal infiltration, precluding IV contrast), prior immunosuppressive therapy (which may have modulated his imaging findings and disease course), and the limitations of CSF analysis despite use of flow cytometry. A renal biopsy in this case may have yielded a more timely diagnosis, as a matter of speculation. Clinical improvement was reported in 11 patients with cauda equina lymphoma with use of chemotherapy and rituximab (Rituxan, Genentech) once diagnosis was ascertained; this suggested that therapy is not futile, though palliation should remain the primary goal. Extra-nodal lymphoma should be strongly considered in patients presenting with an otherwise cryptic cauda equina syndrome, and biopsy of compromised organs or those with signs of infiltration should accompany complete CSF analysis (including flow cytometry) and bone marrow biopsy. This approach may maximize the chance of obtaining a timely diagnosis to allow initiation of antineoplastic therapy, which may provide palliation or even prolongation of survival.


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Lymphomatous Meningitis as a Presentation of Non-Hodgkin Lymphoma

Marc C. Chamberlain, MD

Department of Neurology and Neurosurgery
University of Washington/Fred Hutchinson Cancer Center
Seattle, Washington

Address correspondence to: Marc C. Chamberlain, MD, Fred Hutchinson Cancer Center Seattle Cancer Care Alliance, 825 Eastlake Ave E, MS: G4-940, Seattle, WA 98109; Phone: 206-288-8280; Fax: 206-288-2000; E-mail:

The case report by Mandawat and colleagues1 is instructive for several reasons. Firstly, and as illustrated in the case report, cancer, whether solid or hematologic, may rarely initially present with neurologic dysfunction.2-5  The case under discussion was an unusual and uncommon neurologic disorder affecting the terminal spinal cord—the cauda equina. The cauda equina comprises spinal nerve roots within the lumbar cistern that exit the subarachnoid space and innervate lumbar and sacral dermatomes.6-8 The syndrome manifests as asymmetric sensory and lower motor neuron dysfunction with late-appearing paraplegia and incontinence, as seen in the case presented. Recognizing that the cauda equina is anatomically within the subarachnoid compartment limits the differential diagnosis to 1 of 3 likely possibilities: an intradural extramedullary spinal cord tumor, an extradural spinal cord mass (tumor or abscess), or a primary meningitic process such as meningitis (neoplastic, infectious, or inflammatory not otherwise specified).6,7 Consequently, the appropriate neurologic work-up for a cauda equina syndrome (CES) would include anatomic imaging of the region of interest (the lumbosacral spine) using magnetic resonance imaging with contrast and lumbar puncture to interrogate cerebrospinal fluid (CSF; to include an opening pressure, cell count, glucose, protein, cytology, and flow cytometry). In the instance that the initial work-up is negative, repeating the above mentioned studies would be appropriate and indicated. If a second work-up is negative, then consideration of ancillary central nervous system–directed testing such as fluorodeoxyglucose positron emission tomography (FDG-PET) is appropriate, as it can resolve disease of nerve roots as seen in neurolymphomatosis. Anatomic causes of the CES, best determined by imaging, include epidural (extradural) metastatic or primary vertebral body tumor (giant cell tumor, chordoma), abscess, hematoma (ie, secondary to trauma and a vertebral body fracture), degenerative spine disease (lumbar stenosis or disc herniation), and intradural extramedullary tumor (ie, myxopapillary ependymoma, peripheral nerve sheath tumor or paraganglioglioma); congenital causes include a tethered filum (cord) or diastematomyelia. Meningitic syndromes giving rise to the CES may include neoplastic meningitis, infectious meningitis (mycobacterium, fungal, cytomegalovirus, herpes, human T-lymphotropic virus type I ), or inflammatory causes not otherwise specified, such as intra-CSF chemotherapy-related toxicity, sarcoidosis, or Sjogren’s syndrome.

Of interest in the case under discussion is meningitic syndromes caused by neoplasms, particularly lymphomatous meningitis (LM).3-5 LM, like other causes of neoplastic meningitis (leukemic and carcinomatous), is a disorder that affects the meninges (ie, arachnoid and pia-arachnoid) and the CSF compartment, and involves the entire neuraxis (spine, brain, and exiting nerves). Neoplastic meningitis in the majority of case series most often presents with spinal cord dysfunction (approximately 60%) and commonly a CES. LM may represent a primary CNS lymphoma, though a purely spinal cord and meningitic syndrome is quite rare (<5%). More commonly, LM is a manifestation of leptomeningeal metastasis from a systemic lymphoma and primarily, as in the case under discussion, from a diffuse large B-cell lymphoma. When LM is seen in the context of systemic lymphoma, discovery occurs overwhelmingly after diagnosis, during systemic treatment, and usually within 6 months of diagnosis while on treatment. It is recognized that there are patients with systemic lymphoma at high risk of LM; however, at present, there are no agreed upon criteria for performing upfront CNS staging that includes a lumbar puncture. CSF analysis for lymphoma is best determined by flow cytometry, a CSF volume-independent but laboratory-dependent test most useful for hematologic tumors metastatic to the leptomeninges. In rare instances, CSF cytology (a volume-dependent test requiring 10 mL or more of CSF) will be positive and flow cytometry will be negative. Nonetheless, there exists a fraction of patients with negative CSF and MRI that appears to have LM clinically, such as the case under discussion. A steroid-responsive disorder, at least with respect to neoplastic meningitis, is highly suggestive of LM, but like other inflammatory meningitides, it is confounding correct interpretation. Meningeal biopsy is rarely utilized, but in patients without a clear etiology for a CES, it may be indicated, as in the present case. As mentioned above, FDG-PET may provide evidence of extraneural disease not otherwise seen with computed tomography imaging and may demonstrate disease in the CNS not seen with MRI. As in the present case, a window of opportunity for treatment exists, and delay or failure to make the diagnosis in a timely manner may result in fulminant disease and clinical decline that is no longer responsive to therapy. Metastatic lep-tomeningeal disease in general is underrecognized, underdiagnosed, and undertreated, as this case report vividly illustrates.


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