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Table of Contents    
CASE REPORT
Year : 2021  |  Volume : 69  |  Issue : 2  |  Page : 497-499

Primary Central Nervous System Lymphomatoid Granulomatosis Presenting as Diffuse Corpus Callosum Lesions


Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 JingWu Road, 250021 Jinan, Shandong, P.R. China

Date of Submission23-Mar-2020
Date of Decision17-Aug-2020
Date of Acceptance16-Jan-2021
Date of Web Publication24-Apr-2021

Correspondence Address:
Dr. Xiaohui Liu
Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 JingWu Road, 250021 Jinan, Shandong
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.314578

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 » Abstract 


Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease characterized by angiocentric and angiodestructive infiltrate. It primarily affects the lung and sometimes may also affect the central nervous system (CNS), skin, kidney, liver, etc., but the involvement of lymph nodes and/or bone marrow is extremely rare, and if present, other diagnoses are usually considered. Isolated CNS involvement is very rare, and its pathogenesis and biological behavior have been controversially discussed. Here, we report a 46-year-old man with diffuse and symmetrical corpus callosum involvement. The histopathological findings were in keeping with LYG. Since there was no evidence of involvement of other organs, he was diagnosed with primary CNS-LYG. He responded well to steroids and his symptoms improved significantly. We also conduct an English literature review to provide clues for the diagnosis and treatment of this disease.


Keywords: Central nervous system, imaging, lymphomatoid granulomatosis, neuropathology, primary
Key Messages: Primary CNS-LYG should be considered in the differential diagnosis of diffuse corpus callosum lesions, albeit rarely. Histopathological examination remains the main method for the diagnosis and assessment of primary CNS-LYG.


How to cite this article:
Xiang Y, Li J, Sun Q, Liu X. Primary Central Nervous System Lymphomatoid Granulomatosis Presenting as Diffuse Corpus Callosum Lesions. Neurol India 2021;69:497-9

How to cite this URL:
Xiang Y, Li J, Sun Q, Liu X. Primary Central Nervous System Lymphomatoid Granulomatosis Presenting as Diffuse Corpus Callosum Lesions. Neurol India [serial online] 2021 [cited 2021 May 16];69:497-9. Available from: https://www.neurologyindia.com/text.asp?2021/69/2/497/314578




Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease known for its angiocentricity and angioinvasiveness.[1] It most often involves the lung, followed by the central nervous system (CNS), skin, kidney, and liver,[1] but CNS alone is extremely rare and its clinicopathological features have not yet been fully elucidated. Radiologically, primary CNS-LYG manifests as mass-like or diffuse infiltrating lesions. Lesions involving the corpus callosum are rarely reported. Here, we present our case of primary CNS-LYG with diffuse and symmetrical corpus callosum lesions, discussing the imaging findings, neuropathological features, diagnostic key-points, and therapeutic options in light of the pertinent literature.


 » Case History Top


A 46-year-old man was referred to our hospital in May 2019 for paroxysmal right limb weakness which started 40 days ago. Physical examination revealed that except for the bilateral Babinski sign, there were no other positive findings. Brain MRI showed diffuse abnormal signals throughout the corpus callosum, and the frontal and parietal lobes were also affected. Gadolinium-enhanced T1-weighted imaging revealed multiple punctate, linear, and ring enhanced in the body of the corpus callosum and adjacent regions [Figure 1]. Laboratory evaluation showed that the erythrocyte sedimentation rate was 43 mm/h (normal range, [0–12] mm/h). No obvious immunosuppression or autoimmune disease was found in this patient. Chest CT, ultrasonography of abdomen and superficial lymph nodes, and bone marrow aspiration test were all in a normal range. Lumbar puncture examination showed a pressure of 190 mm H2O. Cerebrospinal fluid (CSF) analysis showed colorless and transparent fluid with an increase in the number of nucleated cells (14 × 106/L; normal range, [0–8] × 106/L, 10% monocytes, 60% large lymphocytes, 30% small lymphocytes), normal glucose, protein, and chloride level. There were no positive findings in CSF culture and cytology analysis.
Figure 1: T2-weighted (a), fluid-attenuated inversion recovery (b) imaging showed diffuse abnormal signals throughout the corpus callosum, and the frontal and parietal lobes were also involved. Gadolinium-enhanced T1-weighted brain magnetic resonance imaging (c-e) revealed multiple punctate, linear, and ring enhanced in the body of the corpus callosum and adjacent regions; brain MRI reviewed 3 months later (f) showed significant shrinkage of the lesions

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Histopathological examination of the right corpus callosum biopsy demonstrated that a large number of lymphocytes infiltrated in and through blood vessels and formed perivascular cuffing, causing damage to the vessel walls and narrowing of the lumen. Immunohistochemically, perivascular infiltrates were predominantly CD3-positive T lymphocytes, followed by CD20-positive B lymphocytes. The proliferation rate detected with Ki-67 antigen was about 5%. There was no obvious nuclear atypia in lymphocytes. The histopathological findings were in keeping with LYG [Figure 2]. Serological EBV IgG titers were positive, while EBV IgM titers were negative. Despite serological evidence of prior EBV exposure, in situ hybridization showed negative for the EBV-encoded RNA. Since there was no evidence of involvement of other organs, the diagnosis of primary CNS-LYG was thus established. He was given methylprednisolone 1000 mg/day for 5 days, then replaced with oral prednisone 60 mg/day, and gradually reduced to a maintenance dose of 10 mg/day. The symptoms were significantly improved. He remained under imaging surveillance, and brain MRI reviewed 3 months later showed significant shrinkage of the lesions [Figure 1]. In the follow-up of 10 months, he successfully completed the prednisone tapering and has since continued to remain in good condition without recurrence or exacerbation.
Figure 2: Histological features of brain biopsy specimens from the right corpus callosum. Hematoxylin and eosin staining showed angiocentric lymphocytic infiltrates and formed perivascular cuffing (a and b). The perivascular infiltrates were predominantly CD3-positive T lymphocytes (c), followed by CD20-positive B lymphocytes (d). EBV-encoded RNA in situ hybridization showed negative (e). Bars indicate 100 (b and e), 200 (a and c), or 400 μm (d)

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 » Discussion Top


Primary CNS-LYG is considered heterogeneous with pathogenesis and biological behavior controversially discussed. To date, research on primary CNS-LYG has been limited to case reports and small case series.

Primary CNS-LYG can affect any part of the CNS without specificity and may show various clinical symptoms due to different involved sites. Diffuse corpus callosum involvement is very rare in primary CNS-LYG and is usually associated with aggressive tumors, demyelination, and traumatic brain injury.[2] Its appearance in brain plain scan CT and MRI is diverse and nonspecific, and the multiple punctate and linear enhancement is just a relatively characteristic feature of LYG, which may represent the involvement of perivascular tissue and the small vessel wall.[3] More and more imaging techniques have been used in the LYG study. Fujimaki et al.[4] suggested that T2*-weighted MRI may be a useful method for differential diagnosis of CNS-LYG. Nishihara and coworkers believed that the mismatch accumulation between 18F-fluorodeoxyglucose positron emission tomography (PET) scan and methionine (MET)-PET scan was characteristic of LYG.[5] However, the value of advanced imaging techniques for primary CNS-LYG requires future clinical research on a large number of patients.

Laboratory findings of LYG are usually nonspecific and insufficient to confirm the diagnosis. Histopathological examination remains the primary method for diagnosing LYG and the classical histomorphological features include polymorphic infiltrate of atypical lymphoid cells, angiocentricity, angiodestruction, coagulative necrosis, etc.[6]

The histopathological findings of our patient showed angiocentric infiltrates of numerous lymphocytes, formation of perivascular cuffing, destruction of the vessel walls, and the perivascular infiltrates were predominantly CD3-positive T lymphocytes, followed by CD20-positive B lymphocytes, which was consistent with LYG.

The disease most needs to be differentiated from our patient is primary angiitis of the central nervous system, which can also manifest as the lymphocyte-predominant inflammatory infiltrate around and within CNS blood vessel walls and lead to the destruction of vessel walls.[7] However, it may also contain a certain number of granulocytes and eosinophils, which are absent in primary CNS-LYG.

The histological grading of LYG is assigned with a scale of I–III, on the basis of the relative proportion of large lymphoid cells, the number of EBV-positive B cells, and the amount of necrosis.[8] Accurate grading is of great significance for predicting the course of the disease and guiding treatment. Our pathological specimen was consistent with grade I. Melani C et al.[9] found through immunoglobulin gene rearrangement (IGR) studies using PCR that low-grade LYG was typically polyclonal, while high grade was usually oligoclonal or monoclonal. Unfortunately, we did not test for IGR.

No official therapeutic approach has been established for LYG. Current treatment strategies of LYG are largely based on its histological grading and underlying pathobiology.[9] Low-grade (grades I and II) LYG was assumed to be immune dependent, so agents like interferon alpha-2b (IFN-α) that enhance the immune response to EBV can be considered,[10] while high-grade (grade III) LYG was assumed to be relatively immune independent, requiring cytotoxic immunochemotherapy.[9] Hematopoietic stem cell transplantation may be considered in patients with primary refractory or multiple relapses, but its efficacy has not been fully determined.[9]

Our patient chose to try steroids though steroids in combination with IFN-α were recommended. He responded well to steroids, and there is no evidence of recurrence yet. A better understanding of the biological properties of primary CNS-LYG paves the way for the development of novel therapies.


 » Conclusions Top


We present here a rare case of primary CNS-LYG, whose condition improved significantly with steroids, but final evaluation after a long-term follow-up is still needed. The imaging findings of primary CNS-LYG are diverse and nonspecific, and in patients with diffuse and symmetrical corpus callosum involvement, the possibility of LYG should be considered. Histopathological examination still remains the primary method for the diagnosis and assessment of this disorder.

Financial support and sponsorship

The study was supported by the Key Technology Research and Development Program of Shandong (Project numbers: 2011GGH21838, 2015GGH318020, 2016GSF201068).

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Song JY, Pittaluga S, Dunleavy K, Grant N, White T, Jiang L, et al. Lymphomatoid granulomatosis--A single institute experience: Pathologic findings and clinical correlations. Am J Surg Pathol 2015;39:141-56.  Back to cited text no. 1
    
2.
Ho ML, Moonis G, Ginat DT, Eisenberg RL. Lesions of the corpus callosum. AJR Am J Roentgenol 2013;200:W1-16.  Back to cited text no. 2
    
3.
Gaha M, Souillard-Scemama R, Miquel C, Godon-Hardy S, Naggara O, Meder JF. MR imaging of the brain and spinal cord in lymphomatoid granulomatosis: A case report and review of the literature. J Neuroradiol 2013;40:364-7.  Back to cited text no. 3
    
4.
Fujimaki M, Kawajiri S, Ichikawa K, Tomizawa Y, Nakazato T, Noda K, et al. Lymphomatoid granulomatosis with central nervous system involvement successfully treated with cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab (CHASER therapy) followed by brain irradiation: A case study. CNS Neurosci Ther 2015;21:610-2.  Back to cited text no. 4
    
5.
Nishihara H, Nakasato M, Sawa H, Murakami H, Yamamoto D, Moriyama K, et al. A case of central nervous system lymphomatoid granulomatosis; characteristics of PET imaging and pathological findings. J Neurooncol 2009;93:275-8.  Back to cited text no. 5
    
6.
Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: A clinicopathologic study of 152 cases. Cancer 1979;43:360-73.  Back to cited text no. 6
    
7.
Salvarani C, Brown RD Jr, Hunder GG. Adult primary central nervous system vasculitis. Lancet 2012;380:767-77.  Back to cited text no. 7
    
8.
Lipford EH Jr, Margolick JB, Longo DL, Fauci AS, Jaffe ES. Angiocentric immunoproliferative lesions: A clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 1988;72:1674-81.  Back to cited text no. 8
    
9.
Melani C, Jaffe ES, Wilson WH. Pathobiology and treatment of lymphomatoid granulomatosis; A rare EBV-driven disorder. Blood 2020;135:1344-52.  Back to cited text no. 9
    
10.
Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood 1996;87:4531-7.  Back to cited text no. 10
    


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