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Pathology International 2015

doi:10.1111/pin.12242

Case Report

Epstein-Barr virus-positive diffuse large B-cell primary central nervous system lymphoma associated with organized chronic subdural hematoma: A case report and review of the literature

Katsuharu Kameda,1 Tadahisa Shono,1 Soh Takagishi,1 Shinji Kono,2 Takatoshi Aoki,3 Yoshikiyo Ito,3 Tomohiko Kamimura,3 Yasuo Sugita4 and Koichi Ohshima4 Departments of 1Neurosurgery, 2Pathology, and 3Hematology, Harasanshin Hospital, Fukuoka, and 4Department of Pathology, Kurume University School of Medicine, Kurume, Japan

We here report on a rare case of Epstein-Barr virus (EBV)positive diffuse large B-cell lymphoma (DLBCL) detected in both brain parenchyma and in an organized chronic subdural hematoma (OCSH). A 96-year-old man diagnosed with asymptomatic OCSH in the left frontal convexity was referred to our hospital because of a de novo mass lesion just beneath the OCSH on contrast-enhanced magnetic resonance imaging. The size of the OCSH remained stable. We diagnosed the lesion as a malignant tumor. At surgery, the organized hematoma and the soft fragile tumor were removed. Histological examinations revealed pleomorphic lymphoid cells not only in the brain tissue but also in the OCSH component with tumor necrosis, and these were immunopositive for B-cell markers. In situ hybridization revealed positive signals for EBV-encoded small RNAs, consistent with EBV-positive DLBCL. Since the membranes of the subdural hematoma were fibrous and the tumor progression resulted in necrosis of the tumor, the DLBCL may have originally developed in the OCSH and infiltrated into the brain parenchyma. We believe that this rare case provides crucial information for the understanding of DLBCLs associated with OCSH. Key words: B-cell lymphoma, chronic inflammation, chronic subdural hematoma, Epstein-Barr virus, primary central nervous system lymphoma, pseudocyst

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin’s lymphoma arising from the brain parenchyma, eyes, meninges, or spinal cord in the absence

Correspondence: Katsuharu Kameda, MD, PhD, Department of Neurosurgery, Harasanshin Hospital, Address: 1–8 Taihaku-machi, Hakata-ku Fukuoka City, Fukuoka, 812-0033, Japan. Email: [email protected] Received 25 March 2014. Accepted for publication 20 November 2014. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

of systemic disease. PCNSL represents approximately 4% of all brain tumors, and the incidence of PCNSL has been increasing in recent years, especially in elderly patients.1 On the other hand, there are few reports of diffuse large B-cell lymphoma (DLBCL) or lymphoproliferative disorders (LPD) associated with chronic subdural hematoma (CSH).2–5 Since both the dura and brain tissue lack lymphoid tissue, the pathogenesis of DLBCL derived from these tissues remains unclear. CSH and organized CSH (OCSH) differ both histologically and clinically. CSH is a common type of intracranial hemorrhage, which generally occurs a few months after a head injury, especially in elderly patients, and which derives in a space within the cell layer of the dura border.6 Once this intradural space has been created, the dura border layer proliferates and produces a thin continuous membrane around the space. The subdural hematoma component is a serous fluid derived from the old hemorrhage. Commonly, burr-hole surgery is applied for the treatment of CSH with mass effects. Conversely, OCSH is a long-standing subdural hematoma, in which the membrane of the hematoma is replaced by fibrosis with sinusoidal channels, gradually forming a solid structure. Accordingly, total removal of OCSH by craniotomy is recommended. Herein, we report on a rare case of Epstein-Barr virus (EBV)-positive DLBCL in both the brain parenchyma and OCSH and discuss the clinicopathological features of this unusual phenomenon.

CLINICAL SUMMARY A 96-year-old man was initially admitted to our hospital because of multiple injuries. A systemic computed tomography (CT) scan revealed multiple pelvic fractures and a

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Figure 1 (a) Plain computed tomography image demonstrating a convex lens-shaped mixed density extra-axial mass lesion (arrowheads) at the left frontal convexity 7 months before the second admission. No lesion was observed in the brain parenchyma. (b) At the second admission, a de novo mass lesion (arrows) was noted in the brain parenchyma, located just beneath the hematoma, with extended brain edema (asterisk) and a midline shift to the contralateral side.

lens-shaped subdural hematoma in the left frontal convexity (Fig. 1a). The intracranial hematoma was of mixed density, 5 cm in diameter, and 1.5 cm thick without any noticeable cranial bone fracture. Because the patient experienced no symptoms, the hematoma was observed conservatively. After conservative treatment of multiple pelvic fractures, he was transferred to the rehabilitation department and was uneventfully discharged. Seven months from the initial admission, he was again referred to our hospital due to progressing gait disturbance and appetite loss. Head CT revealed a de novo lesion accompanied by brain edema, located just beneath the left frontal convexity hematoma (Fig. 1b). The size and density of the hematoma were unchanged from the first admission (Fig. 1b). Magnetic resonance imaging (MRI) revealed a mass lesion in the left frontal lobe, which appeared hypointense on T2-weighted images (Fig. 2a) and by contrast enhancement (Fig. 2b). The patient had no history of congenital or acquired immunodeficiency diseases, and the laboratory data showed no signs of immunodeficiency. Additionally, the patient had not been administered any cytotoxic or immunosuppressive agents. His levels of β-2 microglobulin (5.2 mg/L) and soluble interleukin-2 receptor (681 U/L) were slightly elevated, and a systematic enhanced CT scan detected no additional tumors. We performed left frontal craniotomy under general anesthesia to remove the tumor. No apparent tumor invasion was noted in the cranial bone and epidural space, and the dura mater appeared to be intact. Beneath the dura mater, a thick white membrane was observed (Fig. 3a). The membrane continued to the capsule of the organized hematoma and was able to be detached from the dura mater (Fig. 3a). The capsule of the organized hematoma adhered to the arachnoid membrane and pia mater, and a hemorrhagic tumor was

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Figure 2 (a) Magnetic resonance image showing a hypointense brain tumor (arrows) with extended edema (asterisk) just beneath the hematoma, which was hypointense on T2-weighted images. (b) Contrast enhancement of the brain tumor (arrows).

observed in the frontal lobe (Fig. 3b). The intraoperative histological diagnosis using frozen sections was malignant pleomorphic tumor with extensive necrosis (Fig. 3c). Accordingly, we performed gross total removal of the brain tumor and capsulated hematoma (Fig. 3d). The cerebrospinal fluid showed elevation of malignant cells, but no local recurrence was observed upon head MRI. The patient underwent 2 courses of intrathecal injections with methotrexate, cytarabine, and glucocorticoids. The consciousness of the patient improved, but he died 3 months post-operation due to multiple tumor dissemination. An autopsy was not performed.

PATHOLOGICAL FINDINGS Histological examination revealed large pleomorphic immunoblastic-like cells with widespread tumor necrosis. Mitotic figures and multinucleated giant cells were also observed (Fig. 4a,b). Immunohistochemical analyses revealed that the tumor cells were positive for cluster of differentiation (CD)79a and CD20, and negative for CD3, CD4, CD7, and CD8 (Fig. 4c). Furthermore, the lymphoma cells were partially positive for latent membrane protein-1 (LMP1) and positive for Epstein-Barr nuclear antigen-2 (EBNA2) in the nuclei (Fig. 4d). EBV-encode small RNA (EBER) was found to be strongly positive by in situ hybridization (data not shown); accordingly, the histological diagnosis was EBV-positive DLBCL. The results of the cytogenic analyses of B-cell lymphoma (BCL)-6, BCL-2, and interferon regulatory factor 4 (IRF4, also known as MUM1) were all negative. Flow cytometry revealed positivity for CD19, CD22, CD38, and human leukocyte antigen-DR, and negativity for CD5 and CD10, indicating a matured B-cell type lymphoma. No continuity between the intracapsular tumor and brain tumor was noted. The intracapsular component consisted of widespread necrotized

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

OCSH-associated DLBCL

Figure 3 (a) Reflection of the dura mater. A white membrane-encapsulated hematoma was observed. (b) Reflection of the white membrane. Hemorrhage of the brain tumor was observed, and the arachnoid membrane and pia mater were adhered to the white membrane. (c) The muddy, high viscosity component was encapsulated by a thick fibrous membrane (arrowhead); asterisk shows the state after biopsy for intraoperative histological examination. (d) Intraoperative view after removal of the organized chronic subdural hematoma and brain tumor.

Figure 4 (a) Histological examination of the brain tumor showing pleomorphic cells with necrotic tissue and erythrocytes (arrowhead) by low-power field hematoxylin and eosin stain. (b) High-power field hematoxylin and eosin stain showing immunoblastic-like cells with giant cells, (c) which were positive for cluster of differentiation-79a. (d) Positive signals for Epstein-Barr nuclear antigen-2 (EBNA2) were observed in the nuclei.

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lymphoma coexisting with residual lymphoma (Fig. 5a,c). Normal-sized lymphocytes and plasma cells accumulating in the outer membrane of the thick capsule were observed (Fig. 5a). These reactive lymphocytes around the capsule were mainly composed of CD3-positive T-cells (CD8>CD4). The brain tumor and intracapsular tumor were separated by the thick inner membrane of the hematoma (Fig. 5b), and EBNA2-positive cells were detected in the hematoma component, especially in the necrotic tissue center and adjacent to the capsule (Fig. 5d).

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DISCUSSION In this report, we describe a rare case of EBV-positive DLBCL detected not only in brain tissue but also in the sub-capsular space of an OCSH with extensive necrosis. The OCSH was detected by head CT over 6 months prior to the development of the DLBCL. PCNSLs usually localize in the CNS and rarely infiltrate into the dura mater until end-stage disease. Thus, we hypothesize that the DLBCL originally developed in the OCSH before infiltrating into the brain parenchyma.

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

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d Figure 5 (a, b) Thick outer-membrane and inner-membrane composed of fibrous tissue with inflammatory cells, encapsulated necrotic tissue, and erythrocytes. (c) High-power field hematoxylin and eosin stain showing necrotic tissues with residual atypical lymphoid cells. (d) The intracapsular atypical lymphoid cells were positive for Epstein-Barr nuclear antigen-2 (EBNA2) in the nuclei.

There are few cases of DLBCL associated with CSH in the literature2–5 (Table S1). These reported cases, as well as the case presented herein, indicate that DLBCL is more likely to be detected in organized hematomas than in serous hematomas. In 1990, Reyes et al. first reported a case of malignant lymphoma associated with CSH.4 They described this hematoma as ‘a thick white membrane enclosing a yellow-green crumbly hematoma’ and removed it through craniotomy; accordingly, the hematoma was defined as an OCSH. Unlike in our case, however, no infiltration into the brain parenchyma was observed in their case. Gotoh et al. reported a case of extra-axial primary DLBCL associated with calcified CSH. They detected lymphoma mainly in the dura mater adhered to the outer membrane of the organized hematoma.3 We have recently reported a case of EBV-positive LPD associated with OCSH.5 Therefore, we hypothesized that the organization of the hematoma plays a crucial role in the pathogenesis of DLBCL associated with OCSH. Exceptionally, Alimehmeti et al. reported on a single case of epidural extension of B-cell non-Hodgkin’s lymphoma with underlying serous hematoma.2 In their case, the tumor was localized in the epidural space. Although the pathogenesis of DLBCL associated with CSH remains unclear, chronic inflammation, immunosuppression, and EBV infection have been implicated as potential underlying mechanisms.3–5 CSH reportedly shows some characteristics of inflammation in its organization, including local elevation of inflammatory cytokines.7 This persistent inflammatory state in which DLBCL develops has some similarity to the World Health Organization (WHO) category of DLBCL associated with chronic inflammation (DLBCL-CI).8

Pyothorax-associated lymphoma, which is the prototypic form of DLBCL-CI developing in the pleural cavity, typically occurs after a long latency interval after artificial pneumothorax. However, in our case, very few inflammatory reactive lymphocytes were observed in the intracapsular space, whereas chronic inflammation certainly contributed to the organization of the cyst membrane of the hematoma. DLBCL has been reported to develop in a number of closed spaces, including renal pseudocysts, splenic false cysts, long-standing hydroceles, atrial myxomas, and metallic-implant wear debris.9–11 Boroumand et al. recently reported two cases of DLBCL associated with pseudocysts which showed little association with chronic inflammation in the pathologic specimens.9 They also mentioned that chronic inflammation might not be essential for the pathogenesis of DLBCL detected within pseudocysts.9 The clinical scenarios of these two cases differed considerably compared with those of reported cases categorized as DLBCL-CI, which included prosthetic cardiac valves, metallic implants, and surgical mesh implants among others.11–13 They speculated that the closed space within which these DLBCLs arise is adequate to wall off a cytotoxic T-cell response from the neoplasms, resulting in local immunodeficiency.9 In the present case, histological findings closely resembled that of DLBCL associated with pseudocyst in that the DLBCL existed in the closed space and was only mildly associated with inflammation. Focusing on the time course of this disease, DLBCL associated with pseudocysts or OCSH may present an end-stage of DLBCL associated with chronic inflammation. For this reason, chronic inflammation might not be a prominent feature.

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

OCSH-associated DLBCL

We have recently investigated the role of EBV in the pathogenesis of PCNSL in immunocompetent patients,14 and we found that the LMP1 oncogene and the EBNA2 strain type play important roles in the tumorigenesis of EBV-positive PCNSL.14 In the present case, both the tumor cells in the brain parenchyma and in the OCSH were positive for LMP1 and EBNA2. These results implicate the viral latency as phenotype III in our case. Most cases of DLBCL-CI and DLBCL associated with pseudocysts have had latency phenotype III. Since these oncogenes, when expressed on EBVinfected B-cells, lead to the B-cells being attacked by cytotoxic T-cells, an immunosuppressive state was also assumed in the present case. Interestingly, EBER-positive PCNSL has been found to correlate with age-related EBV-associated B-cell LPD (AREB).14 AREB is defined as an EBV-positive monoclonal large B-cell LPD arising in immunocompetent patients aged over 50 years without a known immunodeficiency or history of lymphoma.15 Oyama et al. hypothesized that decreased immune function was associated with the aging processes, such as decreased function of cytotoxic T lymphocyte immune surveillance, which contributes to the pathogenesis of AREB.16 Thus, a decrease in T-cell function associated with aging as well as the immunosuppressive state adjacent to the membrane enclosures of the OCSH may have contributed to the pathogenesis of the present case. Since CSH is a common type of intracranial hemorrhage, especially in elderly patients, the concept of DLBCL associated with OCSH therefore overlaps with that of AREB in terms of the patient age. To our knowledge, this is the first report on OCSHassociated DLBCL infiltrated to the brain parenchyma. Once DLBCL infiltrates outside the OCSH, the prognosis of the disease is known to become poorer. Even in patients treated with high-dose methotrexate chemotherapy and irradiation, the median survival of strongly EBV-positive PCNSL is reported to be as low as 3 months;17 moreover, unlike in EBV-negative DLBCL, conventional chemotherapy has a limited efficacy for AREB.18 Therefore, when DLBCL is detected in the OCSH, total removal of the OCSH is recommended. Currently, craniotomy with membranectomy is the sole reasonable approach for the removal of OCSHs.19 However, this procedure is invasive and is associated with high mortality and morbidity rates.20 Thus, the most appropriate treatment for each individual patient should be considered. In conclusion, based on the present case and the previously reported cases on this topic, we hypothesize that DLBCL develops in the OCSH similarly to DLBCL associated with pseudocysts. However, limited case reports of DLBCL associated with CSH are currently available, and more careful attention to the presence of DLBCL during the observation of OCSH is thus needed.

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DISCLOSURE None declared.

REFERENCES 1 Deckert M, Paulus W, Louis D, Ohgaki H, Wiestler O, Cavenee W. Malignant Lymphomas. WHO Classification of Tumors Pathology & Genetics of Tumours of the Nervous System. Lyon: International Agency for Research on Cancer, 2007. 2 Alimehmeti R, Locatelli M. Epidural B cell non-Hodgkin’s lymphoma associated with chronic subdural hematoma. Surg Neurol 2002; 57: 179–82. 3 Gotoh M, Tsuno K, Handa A, Nishiura T, Ishimitsu H, Nishida A. [Extraaxial primary malignant lymphoma associated with calcified chronic subdural hematoma: A case report]. No Shinkei Geka 2001; 29: 259–64 (in Japanese). 4 Reyes MG, Homsi MF, Mangkornkanong M, Stone J, Glick RP. Malignant lymphoma presenting as a chronic subdural hematoma. Surg Neurol 1990; 33: 35–6. 5 Sugita Y, Ohta M, Ohshima K et al. Epstein-Barr virus-positive lymphoproliferative disorder associated with old organized chronic subdural hematoma. Pathol Int 2012; 62: 412–17. 6 Haines DE, Harkey HL, al-Mefty O. The ‘subdural’ space: A new look at an outdated concept. Neurosurgery 1993; 32: 111–20. 7 Shono T, Inamura T, Morioka T et al. Vascular endothelial growth factor in chronic subdural haematomas. J Clin Neurosci 2001; 8: 411–15. 8 Chan J, Aozasa K, Gaulard P. DLBCL associated with chronic inflammation. In: Swerdlow SH, Campo E, Harris NL et al., eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue. Lyon: International Agency for Research on Cancer, 2008; 243–44. 9 Boroumand N, Ly TL, Sonstein J, Medeiros LJ. Microscopic diffuse large B-cell lymphoma (DLBCL) occurring in pseudocysts: Do these tumors belong to the category of DLBCL associated with chronic inflammation? Am J Surg Pathol 2012; 36: 1074–80. 10 Loong F, Chan AC, Ho BC et al. Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios. Mod Pathol 2010; 23: 493– 501. 11 Valli R, Piana S, Capodanno I, Cavazza A. Diffuse large B-cell lymphoma associated with chronic inflammation arising in a renal pseudocyst. Int J Surg Pathol 2011; 19: 117–19. 12 Fujimoto M, Haga H, Okamoto M et al. EBV-associated diffuse large B-cell lymphoma arising in the chest wall with surgical mesh implant. Pathol Int 2008; 58: 668–71. 13 Miller DV, Firchau DJ, McClure RF, Kurtin PJ, Feldman AL. Epstein-Barr virus-associated diffuse large B-cell lymphoma arising on cardiac prostheses. Am J Surg Pathol 2010; 34: 377–84. 14 Sugita Y, Terasaki M, Niino D et al. Epstein-Barr virusassociated primary central nervous system lymphomas in immunocompetent elderly patients: Analysis for latent membrane protein-1 oncogene deletion and EBNA-2 strain typing. J Neurooncol 2010; 100: 271–9. 15 Nakamura S, Jaffe E, Swerdlow S. EBV positive diffuse large B-cell lymphoma of the elderly. In: Swerdlow SH, Campo E, Harris NL et al, eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue. Lyon: International Agency for Research on Cancer, 2008; 243–244.

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16 Oyama T, Ichimura K, Suzuki R et al. Senile EBV+ B-cell lymphoproliferative disorders: A clinicopathologic study of 22 patients. Am J Surg Pathol 2003; 27: 16–26. 17 Utsuki S, Oka H, Miyajima Y, Kijima C, Yasui Y, Fujii K. EpsteinBarr virus (EBV)-associated primary central nervous system lymphoma: Is incidence of EBV expression associated with median survival time? Brain Tumor Pathol 2011; 28: 145–9. 18 Oyama T, Yamamoto K, Asano N et al. Age-related EBVassociated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: A study of 96 patients. Clin Cancer Res 2007; 13: 5124–32. 19 Rocchi G, Caroli E, Salvati M, Delfini R. Membranectomy in organized chronic subdural hematomas: Indications and technical notes. Surg Neurol 2007; 67: 374–80; discussion 80.

20 Rosenbluth PR, Arias B, Quartetti EV, Carney AL. Current management of subdural hematoma. Analysis of 100 consecutive cases. JAMA 1962; 179: 759–62.

SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 List of the case reports on chronic subdural hematoma associated with diffuse large B-cell lymphoma.

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

Epstein-Barr virus-positive diffuse large B-cell primary central nervous system lymphoma associated with organized chronic subdural hematoma: a case report and review of the literature.

We here report on a rare case of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) detected in both brain parenchyma and in an o...
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