Neuropathology 2017 doi:10.1111/neup.12438 Case Report Primary central nervous system extranodal nasal-type natural killer/T-cell lymphoma with CD20 expression Dujuan Li,1 Fangfang Fu2 and Lifei Lian3* Departments of 1Pathology, 2Radiology, Henan Provincial People’s Hospital (People’s Hospital of Zhengzhou University), Zhengzhou and 3Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China We report a unique case of primary CNS extranodal natural killer/T-cell lymphoma (PCNS ENKTCL) with CD20 expression and the monoclonal rearrangement of Ig heavey chain (IgH) gene. Resection specimens were evaluated using HE-stained sections, immunohistochemistry, in situ hybridization and PCR. Histopathologic examination, immunohistochemistry and molecular studies showed the intermediate-sized lymphoma cells expressing CD2, CD3ε, granzyme B, TIA-1, CD20 and Epstein–Barr virusencoded RNA, with germline T-cell receptor gene and the monoclonal rearrangement of IgH gene. Clinicopathologic and radiographic evaluation indicated the lesion was of exclusive left cerebellar localization. Thus, PCNS ENKTCL with the CD20 expression was diagnosed. ENKTCL with both CD20-positive expression and the monoclonal rearrangement of IgH gene may be mistaken for B-cell lymphoma; thus, the comprehensive evaluation of histomorphology, more extensive immunoproﬁles and molecular studies is essential to reach the correct diagnosis. The rare PCNS ENKTCL shows a highly aggressive nature and a poorer prognosis. Key words: CD20, Epstein–Barr virus, lymphoma, natural killer/T-cell lymphoma, primary central nervous system lymphoma. INTRODUCTION Primary CNS lymphoma (PCNSL) is a relatively rare disease. Among PCNSL, 98% are comprised of B-cell lymphomas,1 and only 2% are T-cell lymphomas (TCL).2 PCNS extranodal natural killer/T-cell lymphoma Correspondence: Lifei Lian, MD, PhD, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Email: firstname.lastname@example.org Received 04 August 2017; Revised 29 September 2017; Accepted 30 September 2017. © 2017 Japanese Society of Neuropathology (ENKTCL) is exceedingly rare, to the best of our knowledge, with only 10 cases reported in the literature.3–12 Aberrant expression of B-cell-associated antigens in TCL is uncommon, but it is well recognized. CD20 expression has been documented in 5–8% of TCL,13 and most of the cases are classiﬁed as peripheral T-cell lymphoma, not otherwise speciﬁed (PTCL, NOS).14 Co-expressing CD20 in ENKTCL is extremely rare, with only ﬁve cases to date.15–19 In this study, we describe a case of PCNS ENKTCL with CD20 expression, in a 27-year-old immunocompetent Chinese man. This case is unique in its occurrence in PCNS ENKTCL, CD20-positive expression, and the identiﬁcation of the monoclonal rearrangement of B-cell receptor (Ig heavy chain (IgH)) gene. PCNSL ENKTCL or CD20-positive expression in ENKTCL is respectively a rare event, but it is unique indeed for both the phenomena to occur concurrently. Moreover, both CD20-positive expression and the presence of the monoclonal rearrangement of IgH in ENKTCL, to our knowledge, have not been previously described. Thus, this is the ﬁrst case of PCNS ENKTCL with CD20-positive expression and the monoclonal rearrangement of IgH gene. We also review ﬁve cases of CD20-positive ENKTCL, as well as 10 cases of PCNS ENKTCL reported in the literature. CLINICAL SUMMARY A 27-year-old Chinese man had presented with complaints of dysphagia, dysarthria and facial weakness for a period of approximately 4 weeks. There was no relevant personal or familial medical history. The patient had been referred to a local clinic and treated with antithrombotics for “ischemic stroke”, but the symptoms did not improve. As a result, the patient was referred to our hospital for examination and treatment. On initial physical examination, no splenomegaly, lymphadenopathy, skin lesion or fever were observed. Sinonasal involvement was not identiﬁed based on the medical history, symptoms and physical examination 2 D Li et al. results. Neurological examination showed the patient had weakness in the left side of the face and bulbar paralysis. A MRI was performed and revealed a mass located in the left cerebellum and was observed to extend into the medulla oblongata. The lesion exhibited hypodensity on T1weighted and hyperintensity on T2-weighted images (Fig. 1A,B), increased signal on diffusion-weighted images (DWI) (Fig. 1C), and slight enhancement with gadolinium (Fig. 1D). Magnetic resonance spectroscopy (MRS) showed a suppressed N-acetylaspartate peak and an increased choline peak (Fig. 1E). The CSF examination was negative for neoplastic cells, with pleocytosis (28 × 106, normal range 0–8 × 106) and slightly elevated protein (65.21 mg/dL, normal range 15–45 mg/dL). The ocular examination was performed and was negative for ocular lymphoma. The patient was immunocompetent and HIV negative. The white blood cell count, hemoglobin level and platelets were all within reference ranges. A bone marrow biopsy sample failed to detect any malignant cells. The epipharyngoscope examination revealed paralysis in the left vocal cord, without neoplasm. Abdominal ultrasonic inspection demonstrated no hepatomegaly or splenomegaly. A whole-body positron emission tomography (PET)-CT scan revealed intense ﬂuorodeoxyglucose uptake in multiple foci in the left cerebellum but no foci of increased uptake elsewhere in the body, including the nasopharynx, or the sinuses. The patient underwent a partial resection of the mass. A diagnosis of PCNS ENKTCL was made. Then, the patient received 28 Gy irradiation and steroid therapy, but the symptoms did not improve. Two months after the operation, the patient presented with dizziness and fever. Peripheral blood cell examination showed white blood cells, red blood cells, platelet and hemoglobin were decreased. The second whole-body PET-CT scan revealed intense ﬂuorodeoxyglucose uptake in multiple foci in the left cerebellum and bone, indicating the recurrence of the lesion and bone marrow involvement. The re-examination of bone marrow aspiration demonstrated bone marrow invasion of the lymphoma cells (46% of unknown cells). Finally, the patient was discharged and died 3 months later. MATERIAL AND METHODS Parafﬁn-embedded sections were stained with HE. Immunohistochemical studies were performed with a variety of antibodies as described below, using heatinduced antigen retrieval on the Nichirei Bioscience Histostainer and Leica Microsystems Bond-III autostainers according to the manufacturer’s instructions. The antibodies used were CD45, CD20, CD79a, CD19, Pax-5, OCT-2, Bob-1, CD2, CD3ε, CD4, CD5, CD7, CD8, CD56, CD30, terminal deoxynucleotidyl transferase (TdT), TIA- 1, granzyme B and anaplastic lymphoma kinase (ALK). To detect the Epstein–Barr virus (EBV)-encoded RNA (EBER), EBV-RNA in situ hybridization was performed on the parafﬁn-embedded sections using EBER probe (BondTM Ready-to-Use ISH, Leica Biosystems, Newcastle, UK). A multiplex real-time PCR study for the detection of clonally rearranged Ig and T-cell receptor (TCR) genes was performed on DNA extracted from the parafﬁn block. Finally, a capillary electrophoresis in polyacrylamide gel by means of the ABI-PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA, US) was carried out. The multiplex PCR design of primers and protocols was performed as previously described.20 PATHOLOGICAL FINDINGS AND RESULTS The histological examination revealed that the intermediate-sized monomorphic atypical lymphoid cells were arranged in a diffuse growth pattern with focal coagulative necrosis and apoptotic bodies (Fig. 2A). The angiocentric growth pattern was seen (Fig. 2B). The tumor cells had irregularly folded nuclei and inconspicuous nucleoli, with a moderate amount of eosinophilic cytoplasm. Mitotic ﬁgures were readily found. In addition, there was a vascular proliferation and the inﬁltration of some histiocytic macrophages. Immunohistochemical studies showed that the tumor cells were strongly positive for the leucocyte marker CD45 and the T-cell markers CD2 and CD3ε (Fig. 2C). Coexpression of CD20 (Fig. 2D) and CD30 were noted in the majority of tumor cells. Moreover, CD20 staining intensity was heterogeneous. However, other B-cell markers, including CD79a, CD19, PAX5, OCT-2 or BOB1, were negative. The tumor cells were positive for the cytotoxic markers such as granzyme B (Fig. 2E) and TIA1. The proliferation marker Ki67 was positive in approximately 85% of lymphoma cells. The tumor cells were negative for CD56, other T-cell markers (CD4, CD8, CD5, CD7), TdT, myeloperoxidase (MPO) and ALK. In situ hybridization for EBER was strikingly positive in almost all the tumor cells (Fig. 2F). PCR-based molecular testing for the detection of clonally rearranged Ig and TCR genes showed the T-cell receptor gamma (TCRγ) gene and beta (TCRβ) gene, or the Ig light chain (Igκ) gene with polyclonal rearrangement, but the IgH gene showed the monoclonal rearrangement (Fig. 3). DISCUSSION We report a case of intermediate-sized lymphoma cells expressing CD2, CD3ε, granzyme B, TIA-1, CD20, CD30 and EBER, with polyclonal rearrangement of TCR gene and the monoclonal rearrangement of IgH gene. The overall ﬁndings favored ENKTCL, despite the expression © 2017 Japanese Society of Neuropathology PCNS ENKTCL with CD20 expression 3 Fig. 1 Radiological investigation of the brain. Magnetic resonance axial T1-weighted imaging of the brain shows a hypointense lesion in the left medullary dorsal (A) with gadolinium enhancement (D). The lesion is hypertense on T2-weighted imaging (B) and diffusionweighted imaging (C). There is no restricted diffusion on apparent diffusion coefﬁcient map. Magnetic resonance spectroscopy of the lesion suppressed N-acetyl-aspartate with an increased choline peak (E). of CD20 and CD30, as well as with the monoclonal rearrangement of IgH gene. To the best of our knowledge, only ﬁve cases of CD20-positive ENKTCL are reported in the literature; however, all are with polyclonal rearrangement of IgH gene. Here, we report the ﬁrst case of ENKTCL with both CD20-positive expression and the monoclonal rearrangement of IgH gene. Not only aberrant expression of the B-cell marker CD20 is described in T/NK-cell lymphomas,21 but also coexpression of T-cell-associated antigens such as CD2, CD3, CD4, CD7, CD8 may be found in B-cell lymphomas.22–24 Furthermore, aberrant expression of Tcell-associated antigens in B-cell lymphomas may be associated with the absence of PAX-5 gene or deregulated PAX-5 activity.25,26 Therefore, in our case, B-cell lymphoma with T-cell-associated antigens should be included as a major differential diagnosis. In the reported cases of B-cell lymphomas with aberrant CD3 expression,23,24 lymphoma cells strongly and diffusely expressed several B-cell © 2017 Japanese Society of Neuropathology markers such as CD20, CD79a, PAX5, OCT-2 and BOB1. In contrast, in our case, except for the positive expression of CD20, the expression of the other B-cell-associated antigens such as CD79a, CD19, PAX5, OCT-2 and BOB-1 were all negative, which does not support a diagnosis of B-cell lymphomas with aberrant CD3 expression. Furthermore, lymphomatoid granulomatosis (LYG) is an EBVassociated lesion characterized by angiocentric and angiodestructive lymphocyte inﬁltration, predominantly involving the lungs and other extranodal sites, such as the CNS. So, LYG should be included as another differential diagnosis. The EBV-positive cells of LYG are of B-cell origin, and express the B-cell-associated antigens such as CD20, CD79a, CD19, PAX5, OCT-2 and BOB-1. However, in our case, EBV-positive cells express typically the T-cell-associated antigens such as CD2, CD3ε, granzyme B and TIA-1, except for CD20. So a diagnosis of LYG was not favored. In addition, the tumor cells possessed the CD30 positive and CD56 negative phenotype in a younger 4 D Li et al. Fig. 2 Histological and immunohistochemical ﬁndings of the tumor tissues. HE staining reveals that the intermediate-sized tumor cells had irregularly folded nuclei and inconspicuous nucleoli, with focal coagulative necrosis and apoptotic bodies (A). The angiocentric growth pattern was seen (B). The tumor cells were positive for CD3ε (C), CD20 (D), granzyme B (E) and Epstein–Barr virus-encoded RNA (EBER) (F). Bar = 20 μm (A–F). patient, consequently leading to an initial diagnosis of anaplastic large cell lymphoma (ALCL). Indeed, it has been reported that ENKTCL may show CD30-positive expression and CD56-negative expression.27 The ﬁndings of the absence of ALK expression and presence of EBER expression do not favor a diagnosis of ALCL. Therefore, Fig. 3 Molecular testing for the gene rearrangement of the immunoglobulin light chain gene and the immunoglobulin heavy chain (IgH) gene. The tumor demonstrates the monoclonal rearrangement (IGH E) of IgH gene. © 2017 Japanese Society of Neuropathology PCNS ENKTCL with CD20 expression in our case, based on the histopathologic features and the expression of CD2, CD3ε, granzyme B, TIA-1 and EBER, a diagnosis of ENKTCL with CD20 expression was favored. Another dilemma encountered in the diagnosis of this case resulted from the observation of TCR polyclonal rearrangement, and, contrarily, with IgH monoclonal rearrangement. In fact, the monoclonal rearrangement of aberrant cell lineages in B-cell or T-cell lymphomas (socalled “lineage inﬁdelity”) has been reported.15,28,29 The percentage of aberrant gene rearrangement is 5% for Bcell lymphomas and 29% for T-cell lymphomas. Garcia et al. reported that 16% of TCL showed the monoclonal rearrangement of IgH gene.28 Therefore, the ﬁnal determination of cell lineage as exempliﬁed by our case needs to be based on the histopathologic and immunophenotypic features. To date, only ﬁve cases of CD20-positive ENKTCL have been reported.15–19 Five were men and one was a woman, with a median age of 53 years (range, 25–78 years). Three were Chinese and the other three were Japanese, Taiwanese and Caucasian, respectively. The tumors arose from the nasal cavity (two cases), stomach (two cases), right thenar (one case) and cerebellum (one case). Five of the six cases showed the polyclonal rearrangement of TCR and IgH, except for our case showing IgH monoclonal rearrangement. Follow-up information available indicated more highly aggressive clinical course; and three patients (3/5) died within 6 months after the diagnosis. However, the case reported by Jiang et al. presented an indolent clinical course with 10 years duration. Because the case number is too small for analysis, it is uncertain whether CD20-positive ENKTCL is related to prognosis or not. The mechanism of CD20 expression in ENKTCL remains unknown. Two hypotheses were proposed to explain the expression of CD20 in ENKTCL. First, CD20 positivity might represent aberrant antigen expression due to the neoplastic process. Second, CD20 expression might indicate neoplastic transformation of a rare cell type that co-expresses CD20 and NK/T cell markers. Recently, a progenitor capable of differentiating into B-cells, T-cells and NK-cells has also been identiﬁed.30 In our case, the tumor cells were strongly positive for CD20 in a heterogeneous staining pattern. The ﬁve cases reported showed also CD20 immunostaining in tumor tissue varied in staining quantity and intensity. Thus, the positivity for CD20 in a heterogeneous staining pattern might reﬂect the CD20 expression possibly as an activation marker by neoplastic NK/T cells. Furthermore, in our case, CD30, another activation marker, was also detected in the tumor cells. In addition, two of the ﬁve cases were CD20 negative in the primary tumors, with acquisition of CD20 © 2017 Japanese Society of Neuropathology 5 expression in dissemination/relapse, which might represent the clonal evolution of a tumor, or neoplastic NK/T cells aberrantly acquiring CD20 positivity in tumor progression. Rituximab, a chimeric monoclonal antibody against CD20, has been widely used in the treatment of CD20positive B-cell lymphomas. However, the efﬁcacy for CD20-positive T/NK-cell lymphomas is yet to be known. Kakinoki et al. proposed that the efﬁcacy of rituximab for CD20-positive TCL may be associated with intensity of CD20 expression in tumor T-cells and its homogeneity in the tumor tissue.31 Unfortunately, none of the six cases were treated with rituximab. Further clinical studies are required to determine whether the addition of rituximab offers any survival advantage to these patients with CD20positive ENKTCL. Composite clinicopathologic and radiographic evaluation indicated the lesion to be of exclusive left cerebellar localization. Thus, our case also represented an extremely rare case of PCNS ENKTCL. Only 10 cases of PCNS ENKTCL are reported in the literature.3–12 Among the 10 cases, there were seven males and three females, similar to the male predominance of ENKTCL, with a median age of 43.5 years (range 25 to 68 years), younger than those patients with ENKTCL (median age, 53 years). Notably, three cases (3/10) occurred in younger males in their twenties. Four patients were Chinese, two Spanish, two African American, one Korean and one Japanese. By imaging studies, ﬁve patients had supratentorial lesions, one pituitary lesions, one spine lesions, two cerebellar involvement, two leptomeningeal involvement. Pathologically, they usually exhibited a vascular-centered inﬁltration accompanied with vascular damage and coagulative necrosis. The tumor cells typically express CD2, CD56, the cytoplasmic ε chain of CD3 but not surface CD3, as well as cytotoxic granule proteins. The presence of EBV infection is nearly invariable. These features were shared by most of the previous PCNS ENKTCL cases, except for two cases reported.3,10 In the case by Ng et al., the tumor cells expressed surface CD3 but not CD56, furthermore, showing evidence of TCR gene monoclonal rearrangement.3 These ﬁndings suggest that this case may be better categorized as a PTCL, NOS. In addition, in the case by Liao et al., EBV infection was not detected in the malignant cells.10 Therefore, the exact diagnosis of this case may be questionable. Although ENKTCL often shows the germline conﬁguration of TCR, ﬁve out of eight PCNS ENKTCL demonstrated monoclonal rearrangement of the TCR gene. Whether PCNS ENKTCL is more prone to show monoclonal rearrangement of the TCR gene is unknown. The molecular genetic characteristics of this tumor may be worth further study. All cases indicated a highly aggressive nature and rapid clinical progression, with a median overall survival of 7 months. Five patients 6 D Li et al. died within 6 months of diagnosis; the longest survival was 18 months, indicating a poorer prognosis than with extracranial ENKTCL. Therefore, it is important to consider this rare tumor in the differential diagnosis of CNSL. In summary, we report the ﬁrst case of PCNS ENKTCL with both CD20-positive expression and the monoclonal rearrangement of IgH gene. This case serves as a cautionary note regarding the diagnostic pitfalls in determining of the lineage of non-hodgkin lymphoma (NHL) using only B-cell or T-cell markers, or gene rearrangement; thus, histomorphology, more extensive immunoproﬁles and molecular studies are needed for an integrated interpretation and accurate diagnosis. The rarity of PCNS ENKTCL and CD20-positive ENKTCL makes it difﬁcult to establish the prognosis and optimal clinical management of this clinical entity. Further studies are required to clarify the biologic and clinical signiﬁcance of rare lymphomas. 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