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.