Introduction
Waldenstrom macroglobulinemia (WM) is a form of lymphoplasmacytic
lymphoma characterized by the malignant proliferation of monoclonal
immunoglobulin M (IgM)-producing B-lymphocytes resulting in a wide
spectrum of complications [1]. WM is a rare disorder with an
estimated incidence rate of 3 per 106 new cases per
year [2]. Although presenting signs and symptoms of this disease can
vary greatly from patient to patient, all are related to bone marrow
infiltration of lymphoplasmacytic cells as well as the effects from a
monoclonal gammopathy causing hyperviscosity, end-organ deposition, and
autoimmune disease [1,2]. Clinical manifestations include
constitutional symptoms such as fevers, night sweats, and unintentional
weight loss as well as symptoms related to anemia and hyperviscosity
such as fatigue, dyspnea, and headaches [1-2]. Neurological
complications associated with hyperviscosity from WM include visual
changes (i.e. blurred vision), vertigo, tinnitus, and peripheral
neuropathy which is most commonly characterized by bilateral and
symmetrical sensory deficits in the hands and feet that can progress to
difficulty writing and gait instability [1-2]. Disease involvement
outside of the bone marrow most commonly affects the lymph nodes and
spleen, with up to 60% of patients developing extramedullary disease
upon relapse [1]. However, direct invasion of the central nervous
system (CNS) with lymphoplasmacytic tumor cells, referred to as
Bing-Neel syndrome (BNS), remains an extremely rare complication of WM
affecting less than 1% of cases [2,3]. Bing-Neel syndrome usually
presents as a feature of relapsing disease and should be suspected when
there is the onset of central neurological deficits such as altered
mentation, cranial nerve deficits, seizure-like activity, gait
disturbances, or even psychiatric disease [2,3]. Symptoms are
usually gradual, progressing over weeks to months, and may be mistaken
as hyperviscosity syndrome or neuropathy [3]. Here, we present a
case of WM with malignant CNS involvement visualized on MRI with
negative CSF studies but confirmed on brain biopsy as BNS.
Case Presentation
A 70-year-old Caucasian female with medical history significant for
stage III chronic kidney disease, transitional cell ureteral cancer
status post left-sided nephroureterectomy, and Waldenstrom’s
macroglobulinemia (WM) presented with complaints of right-sided weakness
associated with paresthesias, dysarthria, and blurry vision of three
weeks duration. Magnetic resonance (MRI) imaging of the brain
demonstrated an enhancing, hypercellular mass centered in the left
thalamus with additional foci of signal abnormality and enhancement in
the cortex of the left frontal lobe and subcortical white matter
[Figure 1]. These findings were concerning for an intracranial
neoplastic process, especially given her history of WM.
Regarding her oncological history, she was initially diagnosed with WM
at the age of 67 after workup for complaints of chronic fatigue revealed
elevated IgM levels (3370 mg/dL) as well as serum hyperviscosity. Bone
marrow biopsy showed a low-grade B-cell lymphoma with plasmacytic
differentiation and 60-70% bone marrow involvement. Neoplastic cells
were found to be lambda restricted and negative for CD5, CD10, and CD23
by flow cytometry. An increased number of lambda predominant cells were
confirmed by flow cytometry and CD138 immunostaining. The patient was
started on first-line therapy with the Bruton tyrosine kinase inhibitor
ibrutinib, however, due to worsening adverse effects she transitioned
therapy to rituximab, an anti-CD20 monoclonal antibody. Unfortunately,
the patient was found to have worsening IgM levels and serum viscosity
while on rituximab monotherapy. Thus, she was restarted on ibrutinib
while continuing rituximab every 3 months and had significant
improvement on this combination of therapy.
She completed two years of maintenance rituximab and reduced-dose
ibrutinib (140 mg) at time of presentation with the most recent IgM
levels of 299 mg/dL prior to the onset of her previously mentioned
neurological symptoms. Given her MRI findings, computed tomography (CT)
imaging of the head, chest, abdomen, and pelvis was completed which
revealed multiple intracranial lesions but no evidence of
lymphadenopathy or neoplastic process elsewhere. She further underwent
lumbar puncture for cerebral spinal fluid (CSF) analysis with flow
cytometry showing mostly T-cells without evidence of B-cell non-Hodgkin
lymphoma. As there remained high suspicion for central nervous system
(CNS) lymphoma, the patient ultimately had a left parietal stereotactic
brain biopsy with pathology findings of diffuse aggressive B-cell
non-Hodgkin lymphoma [Figure 3A]. Immunohistochemical studies were
positive for CD20, CD23, BCL-6, MUM1, and LE1 [Figure 3B] with
approximately 80% of cells expressing Ki-67 proliferation antigen
[Figure 3C]. Fluorescent in situ hybridization (FISH) analysis was
negative for c-MYC, BCL6, or BCL2 gene rearrangements. Lastly, mutation
testing using next-generation sequencing returned positive for MYD88
L265P mutation, suggesting CNS infiltration of the patient’s previously
known WM (i.e. Bing-Neel syndrome) rather than the development of a
primary CNS lymphoma.
The patient was placed on oral dexamethasone 4 mg four times daily with
noticeable improvement in her speech and mobility. Due to the patient’s
poor renal function, she was not a candidate for induction therapy with
methotrexate. Thus, she began treatment with whole brain radiation
therapy (WBRT) to 30.6 Gy while continuing systemic treatment with
ibrutinib. A repeat MRI of the brain two months later demonstrated near
resolution of the patient’s lymphoma with findings of only a few small
foci of nonspecific enhancement adjacent to the biopsy cavity within the
left thalamus [Figure 2]. There was no evidence of intracranial mass
effect, midline shift, or abnormal extra-axial collection.