Primary Central Nervous System Lymphoma Presenting as Growing Intracerebral Hemorrhage

Primary Central Nervous System Lymphoma Presenting as Growing Intracerebral Hemorrhage

Accepted Manuscript Primary central nervous system lymphoma presenting as growing intracerebral hemorrhage Yoshiyasu Matsumoto, MD, Hiroshi Kashimura,...

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Accepted Manuscript Primary central nervous system lymphoma presenting as growing intracerebral hemorrhage Yoshiyasu Matsumoto, MD, Hiroshi Kashimura, MD, Kenta Aso, MD, Hiroaki Saura, MD, Mitsumasa Osakabe, MD, Akira Kurose, MD PII:

S1878-8750(18)31060-X

DOI:

10.1016/j.wneu.2018.05.107

Reference:

WNEU 8168

To appear in:

World Neurosurgery

Received Date: 4 January 2018 Revised Date:

14 May 2018

Accepted Date: 15 May 2018

Please cite this article as: Matsumoto Y, Kashimura H, Aso K, Saura H, Osakabe M, Kurose A, Primary central nervous system lymphoma presenting as growing intracerebral hemorrhage, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.05.107. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Primary central nervous system lymphoma presenting as growing intracerebral hemorrhage

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Yoshiyasu Matsumoto, MD ([email protected])1, Hiroshi Kashimura,

MD ([email protected])1, Kenta Aso, MD ([email protected])1, Hiroaki Saura, MD ([email protected])1, Mitsumasa Osakabe, MD

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([email protected])2, Akira Kurose, MD ([email protected])3

Department of Neurosurgery, Iwate Prefectural Chubu Hospital, Kitakami, Japan

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Department of Diagnostic Molecular Pathology, School of Medicine, Iwate Medical

University, Morioka, Japan 3

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Department of Pathology and Bioscience, Hirosaki Graduate School of Medicine,

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Japan

Corresponding author: Hiroshi Kashimura, MD

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Department of Neurosurgery, Iwate Prefectural Chubu Hospital 17-10 Murasakino, Kitakami, Iwate 024-8507, Japan

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Tel: +81-19-771-1511; Fax: +81-19-771-1414 E-mail: [email protected]

Keywords: intratumoral hemorrhage, lymphoma, primary central nerve system, vascular endothelial growth factor

Running head: Lymphoma presenting as growing intracerebral hemorrhage

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Abbreviation list: CNS, central nerve system; CT, computed tomography; MR, magnetic resonance; T1WI, T1-weighted image; T2WI, T2-weighted image; VEGF,

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vascular endothelial growth factor

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Abstract Background: Hemorrhage at presentation in primary central nervous system (CNS) lymphoma is rare. We encountered a case of primary CNS lymphoma presenting as a

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growing intracerebral hemorrhage.

Case Description: An 80-year-old man presented with mild dysarthria. Computed

tomography (CT) demonstrated a round, high-density mass with surrounding vasogenic

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edema in the left frontal lobe. Although the patient was placed on antihypertensive therapy for suspected subacute subcortical hemorrhage, neurological symptoms

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gradually worsened. CT after 2 weeks revealed that the high-density lesion and surrounding edema had increased in size compared to previous images. The patient had been transferred to our hospital 14 days after admission to another institution. Magnetic resonance (MR) imaging demonstrated a mass lesion comprising hemorrhage of

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different phases in the left frontal lobe. Contrast-enhanced T1-weighted imaging demonstrated a mass lesion with heterogeneous enhancement in the left frontal lobe. The patient underwent craniotomy with gross total removal of the hemorrhagic lesion.

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The histopathological diagnosis was diffuse large-cell non-Hodgkin’s lymphoma and immunohistochemistry showed high immunoreactivity for vascular endothelial growth

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factor (VEGF).

Conclusion: Although exceedingly rare, primary CNS lymphoma can present as

growing intracerebral hemorrhage due to repeated intratumoral hemorrhages. High expression of VEGF and the mass effects of hemorrhage could be associated with the onset and growth of intracerebral hemorrhage. Early evaluation and meticulous observation are important to avoid progressive, life-threatening situations in such cases.

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Introduction Intratumoral hemorrhage is one of the unusual causes of spontaneous intracranial hemorrhage. Although the incidence of intratumoral hemorrhage is high in malignant

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brain tumors such as glioblastoma and metastatic tumors (1), hemorrhage at

presentation in primary central nervous system (CNS) lymphoma is rare (2). We encountered a rare case of primary CNS lymphoma presenting as a growing

Case report History and examination

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intracerebral hemorrhage, and discuss the management of this rare entity.

An 80-year-old, right-handed man presented with a 7-day history of mild dysarthria and was admitted to a local hospital. He had previously received treatment

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for hypertension.

Computed tomography (CT) demonstrated a round, high-density mass surrounded by vasogenic edema in the left frontal lobe (Fig. 1A). Although the patient was placed

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on antihypertensive therapy for suspected subacute subcortical hemorrhage, neurological symptoms gradually worsened. CT after 2 weeks revealed that the

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high-density lesion and surrounding edema had enlarged compared to the previous images (Fig. 1B). From the radiological findings, presence of a brain tumor was suspected and the patient was referred to our department for further examinations 14 days after the original admission to the local hospital. On admission, neurological examination revealed motor aphasia and left hemiparesis. No history of congenital or acquired immunodeficiency was elicited. Routine blood testing including serum levels of CEA, SLX, SCC, ProGRP, and NSE, and cerebrospinal fluid analysis yielded normal

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results. CT of the chest, abdomen, and pelvis yielded negative results. Magnetic resonance (MR) imaging demonstrated a mass lesion comprising hemorrhages of different phases in the left frontal lobe, with significant surrounding vasogenic edema.

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Contrast-enhanced T1-weighted imaging (T1WI) demonstrated a mass lesion with

heterogeneous enhancement in the left frontal lobe, a small, round, enhancing lesion at the right centrum semiovale, and a lesion with cortical laminar enhancement in the left

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parietal lobe. A hemorrhagic lesion, as inferred from MR imaging, was located in the subcortical region of the left inferior portion of the precentral gyrus and the pars

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opercularis of the inferior frontal gyrus (Fig. 2).

Operation

The patient underwent craniotomy under general anesthesia. Under examination

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through a surgical microscope, the inferior precentral sulcus divided the inferior frontal gyrus from the precentral gyrus, which was dissected. The bottom of the sulcus was incised using a navigation system to avoid cortical injury. Gross total removal of the

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hemorrhagic lesion accompanied by rich blood vessels was performed without cortical

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injury. No new neurological deficits were observed postoperatively.

Histopathological examination Histopathological examination of the surgical specimen demonstrated

CD20-positive diffuse large-cell non-Hodgkin’s lymphoma (Fig. 3A). Tumor cell cytoplasm and membrane stained positively for anti-vascular endothelial growth factor (VEGF) antibody (C-1, 1:500; Santa Cruz Biotechnology, Santa Cruz, CA) in nearly all neoplastic cells (Fig. 3B).

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Postoperative course Chemotherapy with high-dose intravenous methotrexate and leucovorin rescue

imaging and had not recurred as of 7 months postoperatively.

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Discussion

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achieved gradual improvement of neurological symptoms. The tumor resolved on MR

Primary CNS lymphoma is relatively rare, representing only 1-2% of all primary

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CNS malignancies (3). The vast majority of primary CNS lymphomas are diffuse large B-cell lymphomas, regardless of the immunological state of the patient. Although primary CNS lymphoma may present as atypical radiological findings, hemorrhage at presentation in primary CNS lymphoma is rare (2, 4). The presence of hemorrhage is

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thus used to exclude primary CNS lymphoma from the differential diagnoses. Recently, intratumoral hemorrhage in primary CNS lymphoma has been observed on T2*-weighted gradient-echo MR imaging or susceptibility-weighted imaging as silent

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hemorrhage (5, 6). Although exceedingly rare, apoplectic onset of hemorrhage is reported as a presentation for primary CNS lymphoma. To date, 6 cases (including our

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own case) of primary CNS lymphoma presenting as symptomatic intracranial hemorrhage have been reported (Table 1) (7-10). The mean age of these patients was 52 years, with a slight male predominance (66.7%). All cases were pathologically diagnosed as diffuse large B-cell lymphoma. Including our case, 5 of 6 hemorrhagic lesions were located in the subcortex, suggesting an atypical location of hypertensive intracerebral hemorrhage. In terms of immunoreactivity to VEGF, expression was not evaluated in 2 cases, and was high in 4 of 6. In contrast to previous cases, preoperative

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neurological status was worsened only in our case, suggesting worsening of edema or a mass effect. In our case, the round hemorrhagic lesion in the left frontal lobe on CT was a

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round, iso-intense area with focal hyperintensity on axial T1WI and a round,

low-intensity area with focal hyperintensity on axial T2-weighted imaging (T2WI). The area appearing isointense on T1WI and hypointense on T2WI was consistent with

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deoxyhemoglobin, while the area appearing hyperintense on T1WI and hypointense on T2WI was consistent with intracellular methemoglobin. The lesion was thus considered

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to comprise different phases of hemorrhage, suggesting repeated bleeding of the primary CNS lymphoma. To the best of our knowledge, radiologically confirmed repeated intratumoral hemorrhage in primary CNS lymphoma has not been described before.

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Intratumoral hemorrhage is thought to originate from fragile vessels traversing necrotic areas or from tumoral invasion of large vessels, leading to thinning and rupture of the vessel wall (1). Several studies have demonstrated an association between

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hemorrhagic presentation and angiogenic phenotype (12). For example, VEGF is one angiogenic marker related to glioblastoma- and metastatic brain tumor-associated

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hemorrhage, contributing to vascular destabilization and permeability changes in the blood brain barrier (1). However, most lymphoma cells in previous reports showed negative or low VEGF immunoreactivity (13). In contrast, a high degree of immunoreactivity to VEGF was detected in lymphoma cells in the specimen obtained after intracranial bleeding (8-10). Hemorrhage in primary CNS lymphoma may therefore have been related to fragile vessels with high expression of VEGF. Clearly, additional mechanisms may have contributed to the growth of intracerebral hemorrhage.

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We thus speculated that mass effects from hemorrhage may have caused occlusion and necrosis of the fragile vessels and resulted in further intratumoral hemorrhage. Further

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evaluation and meticulous observation is mandatory when atypical ICH is diagnosed.

Conclusions

Although exceedingly rare, primary CNS lymphoma can present as growing

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intracerebral hemorrhage. Not only high expression of VEGF, but also the mass effect

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of hemorrhage could be associated with onset and growth of intracerebral hemorrhage.

Conflict of interest

The authors report no conflicts of interest concerning the materials or methods

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used in this study or the findings specified in this paper.

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lymphoma presenting as an acute massive intracerebral hemorrhage: case report with immunohistochemical study. Surg Neurol 2008;70:308-311. 9. Kimura N, Ishibashi M, Masuda T, Morishige M, Abe T, Fujiki M, Kashima K,

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VEGF expression in a case of primary CNS lymphoma. J Neurooncol 2002;58:53-56.

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11. Streletz L, Terzic D, Salem K, Raza A, Deleu D: CNS lymphoma masquerading as hemorrhagic stroke. Clin Neurol Neurosurg 2012;114:262-264. 12. Cheng SY, Nagane M, Huang HS, Cavenee WK: Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor

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isoforms VEGF121 and VEGF165 but not VEGF189. Proc Natl Acad Sci U S A. 1997;28:12081-12087.

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including a patient with a massive intracerebral hemorrhage. Brain Tumor Pathol 2014,31:222-228.

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Figure Legends Figure 1. A) Initial computed tomography (CT) showing a round, high-density mass with surrounded vasogenic edema at the left frontal lobe. B) Follow-up CT performed 2

increased in size compared to the previous images.

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weeks after onset shows that the high-density lesion and surrounding edema have

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Figure 2. Magnetic resonance (MR) image shows A) a round, isointense area with focal hyperintensity on axial T1-weighted imaging (T1WI), B) a round, low-intensity area

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with focal hyperintensity on the axial T2-weighted imaging (T2WI), and C) a well-demarcated, round, low-intensity area in the left frontal lobe on axial T2*-weighted imaging. D) Axial T1WI with contrast medium shows a mass lesion with heterogeneous enhancement in the left frontal lobe. E) Sagittal T2WI shows a tumor (T)

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and relationships to the inferior precentral sulcus (white arrow), ascending ramus of the lateral sulcus (white dotted arrow), pars opercularis of the inferior frontal gyrus (*), precentral gyrus (‡), pars triangularis of the inferior frontal gyrus (†), and the sylvian

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fissure (white arrowheads).

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Figure 3. Material from the hemorrhagic lesion in the left frontal lobe. A) Proliferation of atypical lymphoid cells with medium-sized, round nuclei and scant cytoplasm (hematoxylin and eosin, ×600). B) Marked positivity for cytoplasmic VEGF (C-1, 1:500; Santa Cruz Biotechnology, Santa Cruz, CA) in nearly all neoplastic cells.

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Series (ref. no.)

Age (yr) /Sex

Pathology

Location of bleeding

29/M 49/F 58/F 55/M 41/M

DLBCL DLBCL DLBCL DLBCL DLBCL

lt. frontal subcortex lt. frontal subcortex lt. frontal cortex lt. frontal subcortex rt. midbrain

Present case

80/M

DLBCL

lt. frontal subcortex

Pretreatment

Immunoreactivity

neurological status

of VEGF

stable stable stable stable stable

N/A high high high N/A

progressive

high

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Fukui et al., 1998 (7) Kim et al., 2008 (8) Kimura et al., 2009 (9) Rubenstein et al., 2002 (10) Streletz et al., 2012 (11)

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Table 1 Cases of intracranial hemorrhage due to primary CNS lymphoma

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M, male; F, female; DLBCL, diffuse large B cell lymphoma; lt, left; rt, right; N/A, ; VEGF, vascular endothelial growth factor; N/A, not available

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The study suggests VEGF activity is related to hemorrhage in primary CNS lymphoma.

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Highlights  Hemorrhage at presentation in primary CNS lymphoma is rare.  We report primary CNS lymphoma presenting as a growing intracerebral hemorrhage.  We radiologically confirmed repeated bleeding of primary CNS lymphoma.

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Abbreviation list: CNS, central nerve system; CT, computed tomography; MR, magnetic resonance; VEGF, vascular endothelial growth factor; T1WI, T1-weighted

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image; T2WI, T2-weighted image.