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Observation
May 2008

Lymphomatoid Granulomatosis Involving Central Nervous System Successfully Treated With Rituximab Alone

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Ishiura, Hamada, Goto, Kwak, and Tsuji), Hematology and Oncology (Drs Morikawa, Watanabe, Kako, Chiba, Motokura, Hangaishi, and Kurokawa), Pathology (Dr Shibahara), and Radiology (Dr Akahane), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Arch Neurol. 2008;65(5):662-665. doi:10.1001/archneur.65.5.662
Abstract

Objective  To report the successful treatment of a patient with lymphomatoid granulomatosis (LYG), a rare Epstein-Barr virus–positive lymphoproliferative disorder, using rituximab (anti-CD20 monoclonal antibody). The prognosis for LYG has been reported to be poor, and no satisfactory treatment has been established. Because central nervous system (CNS) involvement of LYG has been known to show poor prognosis, the establishment of an effective treatment for CNS LYG with mild adverse effects is desired.

Design  Case report.

Setting  University hospital.

Patient  A 48-year-old Japanese man presenting with slowly progressive spastic paraparesis diagnosed as LYG involving the CNS and lungs.

Interventions  The patient was treated with rituximab (375 mg/m2, once weekly for 1 month) alone.

Main Outcome Measure  Improvement of the lesions on imaging.

Results  The neurological signs resolved and the lesions in the CNS and lungs were mostly diminished after the rituximab monotherapy without any adverse effects. The patient stayed in remission for 18 months.

Conclusion  Rituximab monotherapy was effective in treating the patient; hence, rituximab should be considered as the initial treatment against LYG involving the CNS.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder characterized by angiocentric and angiodestructive Epstein-Barr virus (EBV)–positive B-cell proliferation associated with extensive reactive T-cell infiltration.1 The common sites of involvement include the lungs, skin, and central nervous system (CNS). To date, no satisfactory treatment has been established and treatments using corticosteroids, chemotherapy, interferon alfa-2b, radiotherapy, and stem cell transplantation have been selected according to patients' conditions.1 The prognosis of LYG is generally poor, because some may evolve to EBV-positive diffuse large B-cell lymphoma. After the involvement of EBV-positive B cells had been established as essential in LYG development, a few reports on treatment with rituximab (a chimeric anti-CD20 monoclonal antibody) were published14; however, the outcome of this treatment for LYG involving the CNS is still undetermined. We herein report a case of LYG involving the CNS and lungs successfully treated with rituximab alone.

REPORT OF A CASE

A 48-year-old man with well-controlled asthma and atopic dermatitis felt pain in both his shoulders 2 years and 9 months before his admission to our hospital. The pain gradually extended to his back and knees. Two years before his admission, he felt weakness in his knees. Eight months before his admission, he started to show gait disturbance. Numbness appeared in his toes on both feet and subsequently spread to his knees. Four months before his admission, he developed bladder incontinence. His gait worsened and he started to need a cane.

On admission to our hospital, his physical examination results were unremarkable except for atopic dermatitis. Neurological examination revealed spastic paraparesis with increased tendon reflexes in all his extremities and positive finger flexor reflexes. His plantar reflexes were extensor. He also had distal dominant dysesthesia of his lower limbs, spastic-type neurogenic bladder, and fecal incontinence. He was not able to run or go up the stairs. He could only walk with a cane for a short distance.

His serum soluble IL-2 receptor level was 550 U/mL (reference range, 167-497 U/mL). Anti–human immunodeficiency virus antibodies were not detected. His other laboratory results were unremarkable. His cerebrospinal fluid showed an elevated protein level (0.097 g/dL [to convert to grams per liter, multiply by 10]) and lymphocytic pleocytosis (28 cells/μL). The cytologic analysis showed no malignant cells. The test results for bacteria, Mycobacterium tuberculosis, and fungi were negative.

His nerve conduction study results, auditory brainstem response, and visually evoked potentials were normal. Short-latency sensory evoked potentials of the right tibial nerve revealed slight elongation of central conduction time (19.6 milliseconds), but those of the left tibial nerve were normal.

Magnetic resonance imaging of his head and spinal cord demonstrated numerous spotty lesions with a marked gadolinium enhancement (Figure 1A-C). Computed tomographic scans revealed nodular lesions in both his lungs, parts of which showed increased uptake rates of [18F]-fluorodeoxyglucose (FDG) by positron emission tomography (Figure 1D and E). Video-assisted thoracoscopic biopsy of his left lung revealed infiltrates predominantly composed of lymphocytes. Immunohistochemical staining for CD3 and CD20 showed the predominance of T cells and a few B cells, respectively. In situ hybridization revealed positivity for the EBV-encoded viral RNA in a few lymphocytes (Figure 2), confirming the diagnosis of grade 1-2 LYG.

Figure 1.
Magnetic resonance images of the head and spinal cord, computed tomographic scans of the lung, and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) of the body before treatment. A, Numerous spotty high-intensity lesions are observed in the pons and cerebellum on a T2-weighted image. B, These lesions are enhanced with gadolinium on a T1-weighted image. The lesions are also observed in the cerebral cortex to a lesser extent. C, A T1-weighted image with gadolinium enhancement of the cervical cord also demonstrates similar lesions. D and E, Nodular lesions are observed in the left lower lung and these lesions show abnormal FDG uptake, for which the maximum standard uptake value is 3.2.

Magnetic resonance images of the head and spinal cord, computed tomographic scans of the lung, and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) of the body before treatment. A, Numerous spotty high-intensity lesions are observed in the pons and cerebellum on a T2-weighted image. B, These lesions are enhanced with gadolinium on a T1-weighted image. The lesions are also observed in the cerebral cortex to a lesser extent. C, A T1-weighted image with gadolinium enhancement of the cervical cord also demonstrates similar lesions. D and E, Nodular lesions are observed in the left lower lung and these lesions show abnormal FDG uptake, for which the maximum standard uptake value is 3.2.

Figure 2.
Histopathologic examination of the lung specimen. A, Lymphocytes infiltrate the regions around the bronchi and blood vessels (hematoxylin-eosin). The infiltrates are predominantly small lymphocytes admixed with histiocytes and occasionally large, atypical lymphoid cells, which are angiocentric and angioinvasive, thus destroying the blood vessels. B, Some of the lymphocytes are positive for Epstein-Barr virus–encoded viral RNA. C and D, CD20-positive B cells (C) are surrounded by a large number of CD3-positive T cells (D).

Histopathologic examination of the lung specimen. A, Lymphocytes infiltrate the regions around the bronchi and blood vessels (hematoxylin-eosin). The infiltrates are predominantly small lymphocytes admixed with histiocytes and occasionally large, atypical lymphoid cells, which are angiocentric and angioinvasive, thus destroying the blood vessels. B, Some of the lymphocytes are positive for Epstein-Barr virus–encoded viral RNA. C and D, CD20-positive B cells (C) are surrounded by a large number of CD3-positive T cells (D).

Although various therapeutic options, including whole-brain irradiation, were considered, we thought that less toxic therapeutic approaches were more appropriate for grade 1-2 LYG. Because the neoplastic B cells expressed CD20, the patient was treated with rituximab (375 mg/m2, once weekly) for 4 weeks. Magnetic resonance images of his head and spinal cord showed marked improvement of the lesions 1 month after the treatment (Figure 3A and B) compared with the lesions in the images obtained before the treatment (Figure 1B and C), followed by further improvement of the lesions 8 months after the treatment (Figure 3C and D). The lesions in the lungs were hardly detected in the computed tomography scans 4 months after the treatment. His pain in his shoulders, back, and hips disappeared. His gait improved and he was able to walk without a cane for several hundred meters. For 18 months, his condition remained stable without recurrence.

Figure 3.
T1-weighted images with gadolinium enhancement of the cerebellum, pons, and cervical cord after treatment. A and B, The pons (A) and cerebellum (B) 1 month after treatment. C and D, The pons (C) and cerebellum (D) 8 months after treatment.

T1-weighted images with gadolinium enhancement of the cerebellum, pons, and cervical cord after treatment. A and B, The pons (A) and cerebellum (B) 1 month after treatment. C and D, The pons (C) and cerebellum (D) 8 months after treatment.

COMMENT

In this patient presenting with slowly progressive spastic paraparesis, numerous spotty lesions were observed in the CNS and lungs. The lesions showed contrast enhancement with gadolinium and FDG accumulation, and biopsy of the lesions in the left lung confirmed the diagnosis of LYG.

The definitive diagnosis of LYG is difficult, partly because of its rarity. The radiographic findings of the patient showing numerous granulomatous lesions in the CNS and lungs are highly suggestive of LYG5 (Figure 1). [18F]-fluorodeoxyglucose accumulation in these lesions further confirmed the diagnosis.3

A characteristic clinical feature of the patient was mild neurological signs of spastic paraparesis (he could walk even on admission) despite the striking radiographic findings. Consistent with mild neurological signs, only mild deteriorations in electrophysiological studies were observed in the patient. Such features are sometimes observed, for instance, in miliary tuberculosis involving the CNS. These features can also suggest the possibility of LYG.

Although the prognosis of LYG is variable, the median survival of patients with LYG has been shown to be less than 2 years, and CNS involvement, observed in about 30% of patients with LYG,1 indicates poor prognosis. Although aggressive therapies, including chemotherapy, radiotherapy, and stem cell transplantation, have been conducted, no satisfactory standard treatment has been established for the treatment of LYG. Epstein-Barr virus–positive B-cell infiltration has been established as a pathognomonic feature of LYG. Since then, several reports on treatments with rituximab, with or without chemotherapy or radiotherapy, have been made.14 Only 1 report on a patient with CNS LYG treated with rituximab alone3 showed clinical remission for more than 36 months. Although approximately 1% of rituximab seems to pass through the blood-brain barrier and the effects of rituximab on CNS lesions are disputable,6 our patient responded well to rituximab therapy without any adverse effects and his condition remained stable for 18 months, thus strongly suggesting the efficacy of rituximab monotherapy as the initial therapy for low-grade CNS LYG.

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Article Information

Correspondence: Shoji Tsuji, MD, PhD, Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (tsuji@m.u-tokyo.ac.jp).

Accepted for Publication: September 16, 2007.

Author Contributions: Drs Ishiura and Morikawa equally contributed to this work. Study concept and design: Ishiura, Hamada, Kwak, and Tsuji. Acquisition of data: Ishiura, Morikawa, Hamada, Watanabe, Kako, Shibahara, Akahane, Goto, Kwak, Kurokawa, and Tsuji. Analysis and interpretation of data: Ishiura, Hamada, Chiba, Motokura, Hangaishi, Shibahara, Akahane, Goto, Kwak, and Tsuji. Drafting of the manuscript: Ishiura, Morikawa, Hamada, Goto, Kwak, and Tsuji. Critical revision of the manuscript for important intellectual content: Hamada, Watanabe, Kako, Chiba, Motokura, Hangaishi, Shibahara, Akahane, Goto, Kwak, Kurokawa, and Tsuji. Obtained funding: Morikawa and Goto. Administrative, technical, and material support: Shibahara, Akahane, Kwak, and Tsuji. Study supervision: Hamada, Watanabe, Hangaishi, Goto, Kwak, Kurokawa, and Tsuji.

Financial Disclosure: None reported.

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