Stacy, Rebecca C MD, PhD; Jakobiec, Frederick A MD; Hochberg, Fred H MD; Hochberg, Ephraim P MD; Cestari, Dean M MD
Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by clonal lymphoplasmacytoid cells and immunoglobulin M (IgM) heavy chain production (1). Neurologic and ocular involvement can occur by infiltration of WM cells or deposition of IgM in tissues, formation of amyloid deposits, or transformation to more aggressive forms of lymphoma. More than 50% of patients with WM have peripheral nerve involvement. Rarely, WM cells and tissue-bound IgM can involve the lacrimal gland and retina (2) or be associated with discrete masses within the orbit (3-5). Less commonly, WM affects the intracranial tissues. A decade before Waldenström characterized his eponymous disease, Bing and Neel (6) and Bing et al (7) reported 3 patients with intracranial lymphoplasmacytic proliferation without bone lesions. The Bing-Neel syndrome (BNS) designates the intracranial manifestations in patients with WM.
We describe a patient with BNS with diffuse, bilateral infiltration of the orbital fat and optic nerves that preceded the identification of involvement of the meninges, cauda equina, and cerebrospinal fluid (CSF). The orbital infiltrates were nontumefactive and did not produce proptosis. Treatment with intravenous and intrathecal chemotherapy was followed by autologous stem cell transplantation. This case extends the spectrum of manifestations of BNS.
A 47-year-old man was found to have anemia, but an evaluation was unrevealing. Two years later, abdominal CT demonstrated retroperitoneal lymphadenopathy and a CT-guided biopsy showed kappa-restricted small lymphocytes expressing CD19 and CD20 but not CD5, CD10, or CD23. Based on an IgM of 1820 mg/dL, the diagnosis of WM was made. He was treated with rituximab, cyclophosphamide, vincristine, and prednisone without response. He was then treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, leading to a partial remission. Four years after the diagnosis of WM, he developed decreased eye movements in both eyes and was referred to our neuro-ophthalmology service.
The patient reported that for the past year he had experienced intermittent “pressure sensations” behind both eyes. He denied diplopia or other pertinent symptoms. Visual acuity was 20/20 in both eyes with normal color vision (by Ishihara plates), Amsler grid testing, and pupillary reactions. There was no proptosis and the globes were nontender to palpation but slightly resistant to retropulsion symmetrically. Adduction was slightly reduced bilaterally without misalignment on alternate cover testing in primary gaze position. Automated perimetry showed a superior nasal defect in the right eye and a superior arcuate defect in the left eye (Fig. 1). The biomicroscopic and ophthalmoscopic examinations were normal except for an operculated retinal hole in the left eye.
Orbit and brain T1 MRI revealed heterogeneous hypointensity of orbital fat (Fig. 2A). Scattered areas of abnormal hyperintensity on T2 sequences were present in both orbits (Fig. 2B). Postcontrast fat-suppressed T1 images revealed dense diffuse bilateral enhancement of the orbital fat and optic nerves (Fig. 2C, D). The leptomeninges also enhanced (Fig. 2D, arrow).
Right orbitotomy and biopsy of the orbital fat demonstrated a dense infiltrate composed of lymphocytes and lymphoplasmacytoid cells that invaded but did not destroy the septal and lobular architecture of the orbital fat (Fig. 3A). The infiltrating lymphoplasmacytoid cells had small, round, and dark nuclei and surrounded by rims of eosinophilic cytoplasm. Electron microscopy confirmed the presence of mitochondria and many strands of rough endoplasmic reticulum, consistent with antibody production (Fig. 3B). The lymphocytes stained positively for CD20 (a B-cell marker) (Fig. 3C) and BCL-2 (a marker for many non-Hodgkin lymphomas). In situ hybridization showed IgM-positive cells and many scattered kappa cells (Fig. 3D), which also coexpressed the Mu heavy chain. Stains for CD10 (a marker for precursor B-lymphoblastic leukemias and follicular lymphomas) and CD23 (a marker for follicular lymphomas) were negative.
Six weeks later, the patient described episodes of vision loss in the left eye lasting 10-30 seconds. Visual field deficits in both eyes had enlarged, and optic discs had become swollen (Fig. 4A). The MRI was unchanged. Due to the progression in symptoms and worsening visual field deficits, the patient was admitted the next day and treated with methylprednisolone, 1 g/day for 2 days. A lumbar puncture the same day yielded spinal fluid containing 255 mg/dL of protein and 6 white blood cells. When examined by flow cytometry, 30% of CSF cells were marked with CD19 and 20 but none with CD23, CD5, or CD10. Palliative orbital radiation was started one day later in 10 fractions to a total dose of 20 Gy.
These findings were consistent with WM without transformation into a large B-cell lymphoma. Spine MRI demonstrated enhancement in the cauda equina and meninges (Fig. 4B). Parenteral intravenous methotrexate (8 g/mm2 every 10 days) was then administered for 5 cycles. One month after the fifth cycle, visual acuity, pupillary responses, and color testing remained normal and there were no further episodes of transient visual loss. Visual fields had improved, and optic disc edema had resolved without pallor. At this time, a bone marrow biopsy contained 5% lymphoma cells by flow cytometry.
To consolidate the systemic WM response, the patient underwent an in vivo rituximab-purged autologous hematopoietic stem cell transplant. Conditioning chemotherapy 9 days before his procedure began with intravenous bolus of 250 mg/m2 thiotepa per day for 3 days, followed by 0.8 mg/kg intravenous busulfan every 6 hours for 3 days, followed by 60 mg/kg intravenous cyclophosphamide for 2 days.
Seventy-seven days after the transplant, orbit/brain MRI demonstrated stable infiltration of the orbital fat, optic nerves, and meninges. Eighty days after transplantation, CSF had improved, showing a protein of 102 mg/dL and 2 white blood cells. However, neuro-ophthalmic examination revealed worsening of the visual field defects. A single dose of intrathecal cytarabine liposome injection with systemic dexamethasone abolished CSF lymphocytes and reduced protein concentration to 57 mg/dL. No malignant CSF cells were identified on flow cytometry. One month after intrathecal chemotherapy, visual fields had improved and no lymphoma was present on bone marrow biopsy. Six months after transplantation, the patient remains on maintenance cytarabine liposome injection therapy without reappearance of WM and no new visual problems. His last IgM level was 127 mg/dL, within the normal range.
BNS, a rare complication of WM, results from tumor cell infiltration of the CSF or the deposition of WM-associated IgM within the brain and spinal cord. It was first described in 1936 in a patient with infiltration of the spinal cord and medulla by lymphoplasmacytoid cells (6). In the past 70 years, various definitions and classifications of BNS have been proposed. In 1960, Logothetis et al (8) refined the classification of BNS into 5 different subtypes: focal, diffuse, peripheral, subarachnoid hemorrhage, or mixed. Patients with diffuse disease have been classified by us (9) into 2 groups of patients: Group A, those with WM cells invading the brain or CSF, and Group B, a smaller population with WM-associated IgM damage to the white matter of the brain.
Many reports erroneously apply the term BNS to describe focal deficits caused by malignant transformation events of WM. It is important to distinguish Group A presentations from transformation of WM into diffuse large B-cell lymphoma with intracranial involvement, which presents with distinct tumor masses, focal neurological deficits, or seizures. Brain biopsies from transformed patients demonstrate focal neoplastic lymphocytic infiltration of the brain parenchyma (10,11). This was not the case in our patient. His Group A BNS appears to have consisted of WM cells infiltrating the orbital fat and optic nerves. Patients in Group A can have diffuse WM infiltrates into brain or meninges and can present with confusion, fatigue, and personality changes. Neuroimaging in these cases shows meningeal enhancement (12) or white matter changes. Histologic studies from Group A demonstrate lymphocytes or lymphoplasmacytoid cells in the brain stem and meninges (8,13-16). Group B patients have cells in the brain or CSF in numbers insufficient to explain diffuse neurologic impairment, suggesting a causative role for WM-associated IgM, a role analogous to WM-IgM deposition on peripheral nerves.
The reported ocular complications of WM have usually reflected hyperviscosity in the setting of excessive quantities of pentameric IgM, resulting in vaso-occlusive conditions with associated flame-shaped retinal hemorrhages and optic disc edema (5). Rare reports note tumors within the orbit (17), lateral orbital wall (18), eyelid, bulbar conjunctiva (19), and lacrimal gland (2). Histology in these cases has been consistent with WM. Karimi et al (20) reported a case of biopsy-confirmed WM complicated by multiple discrete masses in the soft tissue of both orbits that had infiltrated and replaced normal orbital fat.
Less common than orbital WM cases are those with WM and orbital and intracranial involvement. Kim et al (21) reported such a patient with headache and a cavernous sinus mass. The dura and CSF contained WM cells, but no ophthalmic data were provided. Another patient complained of cloudy vision, confusion, and headaches in advance of decreased acuity, keratic precipitates, vitreous debris, chorioretinitis, and optic disc edema from intracranial hypertension (22). Biopsied brain tissue contained vascular infiltrates of lymphoplasmacytic cells, consistent with WM. The pathological features of the chorioretinitis are unknown. A similar example (13) was a 68-year-old woman with WM and a right sixth cranial nerve palsy, who had enhancement of the leptomeninges and elevated protein in the CSF.
Our patient had histological evidence of WM involving the orbit and CSF with extensive MRI involvement of optic nerves, spinal cord, and meninges. He represents Group A cellular infiltration of BNS, and his cellular form of BNS is characterized by infiltration of the optic nerves, cauda equina, spinal cord and brain meninges, Virchow-Robin spaces, and CSF. This case extends the prior limited definition of BNS, which included only discrete lesions within the intracranial space (23).
Our case is unusual in several regards. Orbital WM has previously been described as discrete masses on imaging, which were associated with proptosis and restricted eye movement (17,18). In contrast, our patient had no discrete tumor mass or evidence of transformation into a higher-grade tumor. Instead, there was diffuse infiltration of the orbital fat without complete obliteration of its constituent lobules. The absence of proptosis suggests an almost equal volumetric replacement of fat by tumor. This pattern of diffuse infiltration has not yet been reported in WM; but this pattern has been documented with non-Hodgkin lymphoma in a patient with multiple myeloma (24) and has been seen in some of our other patients with primary ocular lymphoma. The patient of Karimi et al (20) had multiple discrete bilateral tumor masses. It is possible that our patient represents a later stage of a similar process, as the biopsy in the case of Karimi et al (20) showed patchy deposits of tumor cells in nonobliterated fat.
Our case extends the signs, symptoms, and examination of Group A patients with BNS to include ophthalmic manifestations (9). The process developed with asymptomatic visual field defects and MRI evidence of infiltrative optic neuropathy. With progression, the visual field defects worsened and transient visual loss occurred. The diffuse enhancement of the optic nerve from the globe to the orbital apex, beyond the intraconal fat, suggests an infiltrative process, which may have been ameliorated by treatment. Alternatively, we cannot exclude the possibility of nerve compression by infiltrates within the orbital fat.
Once diagnostic criteria for BNS have been accepted, more rigorous trials of treatment methods may proceed. To date, clinicians have explored intravenous and intrathecal chemotherapy and whole-brain radiation, with varying results (11-13,21). Treatment with high-dose methotrexate, orbital radiation, and corticosteroids resulted in reduction of visual symptoms in our patient. The intracranial component of the disease responded to high-dose conditioning regimens prior to autologous stem cell transplantation. However, complete response was elusive. Worsening visual field defects and persistent CSF tumor cells prompted therapy with intrathecal cytarabine liposome injection, which led to a favorable response.
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