研究者詳細 - 榊原　綾子

Anaplastic variant of diffuse large B-cell lymphoma: Reappraisal as a nodal disease with sinusoidal involvement 査読有り

Megahed, NA; Kohno, K; Sakakibara, A; Eladl, AE; Elsayed, AA; Wu, CC; Suzuki, Y; Takahara, T; Kato, S; Nakamura, S; Satou, A; Asano, N

PATHOLOGY INTERNATIONAL 69 巻 ( 12 ) 頁： 697 - 705 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pathology International

Anaplastic variant (av) of diffuse large B-cell lymphoma (DLBCL) is morphologically defined in the 2017 World Health Organization classification, but still an enigmatic disease in its clinicopathologic distinctiveness, posing the differential diagnostic problem from gray zone lymphoma (GZL) and classic Hodgkin lymphoma (cHL). Thirty-one cases previously diagnosed as avDLBCL were reassessed. Of these, 27 (87%) and 4 (13%) were node-based and extranodal diseases, respectively. They were further reclassified into nodal avDLBCL (n = 18), nodal CD30+ DLBCL with T-cell/histiocyte-rich large B-cell lymphoma-like features (CD30+ DLBCL-THRLBCL) (n = 6), GZL with features intermediate between DLBCL and cHL (n = 3) and CD30+ extranodal DLBCL, NOS (n = 4). The nodal avDLBCL cases had a sheet-like proliferation of large cells and/or Hodgkin/Reed-Sternberg (HRS)-like cells in 12 (67%) notably with a sinusoidal pattern in 16 (89%). They showed an expression of CD20 and/or CD79a in all and CD30 in 15 of 18. All of them were negative for PD-L1 on tumor cells, although HRS-like cells showed negativity or partial loss of other B-cell markers to varying degrees. The present study highlighted the distinctiveness of the nodal avDLBCL with sinusoidal pattern, but without neoplastic PD-L1 expression, which provide refined diagnostic criteria for a more precise pathologic and clinical characterization of this disease.

DOI： 10.1111/pin.12871

Divergence and heterogeneity of neoplastic PD-L1 expression: Two autopsy case reports of intravascular large B-cell lymphoma 査読有り

Sakakibara, A; Inagaki, Y; Imaoka, E; Sakai, Y; Ito, M; Ishikawa, E; Shimada, S; Shimada, K; Suzuki, Y; Nakamura, S; Satou, A; Kohno, K

PATHOLOGY INTERNATIONAL 69 巻 ( 3 ) 頁： 148 - 154 2019年3月

記述言語：英語出版者・発行元：Pathology International

Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease, but the neoplastic PD-L1 expression on tumor cells may vary among cases. We evaluated 10 IVLBCL autopsy cases for neoplastic PD-L1 expression, and had positive results in two cases. In one case, neoplastic PD-L1 expression (SP142, 28-8, and E1J2J clones) was dependent on the organ and anatomical site (capillaries vs. vessels) of the tumor tissue. Neoplastic PD-L1 expression was found in tumor cells located in capillaries in the central nervous system, pituitary gland, kidneys, lung, and gastrointestinal tract; sinuses/sinusoids of the spleen, liver, bone marrow, and lymph nodes; and an extravascular location. However, this expression was not detected in tumor cells located in the adrenal gland, thyroid gland, pancreas, ovaries, uterus, pleura, and small or larger-sized vessels of the lung. The other case showed constant neoplastic PD-L1 expression on the tumor cells, and in addition to the affected organs, capillaries, and vessels with two anti-PD-L1 antibodies (28-8 and E1J2J, but not SP142). The divergence and heterogeneity of neoplastic PD-L1 expression were clearly demonstrated in our cases. To the best of our knowledge, this is the first description of divergent neoplastic PD-L1 expression among the affected organs and anatomical sites in IVLBCL.

DOI： 10.1111/pin.12757

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma arising in patient with a history of EBV-positive mucocutaneous ulcer and EBV-positive nodal polymorphous B-lymphoproliferative disorder 査読有り

Daroontum, T; Kohno, K; Inaguma, Y; Okamoto, A; Okamoto, M; Kimura, Y; Nagahama, M; Sakakibara, A; Satou, A; Nakamura, S

PATHOLOGY INTERNATIONAL 69 巻 ( 1 ) 頁： 37 - 41 2019年1月

記述言語：英語出版者・発行元：Pathology International

Elderly patients with Epstein-Barr virus (EBV) infection are at increased risk for developing B-cell lymphoproliferative disorder (B-LPD) due to immunosenescence. Here, we describe a case of a 75-year-old man who developed an EBV-positive (EBV+) mucocutaneous ulcer (EBVMCU) in the gingiva with spontaneous regression. Eighteen months after regression, he had a cervical lymph node enlargement that was diagnosed as EBV+ nodal polymorphous B-LPD, Ann Arbor stage IA. Clinicians decided to observe his clinical course without any treatment. Fourteen months later, the patient developed EBV-positive diffuse large B-cell lymphoma (DLBCL), Ann Arbor stage IIA, and received six courses of age-adjusted dose chemotherapy and achieved a complete remission. No evidence of a clonal relationship was found among these three lesions by standard polymerase chain reaction (PCR) analysis for immunoglobulin heavy chain. However, they all had expression of PD-L1 in the EBV+ large B-cells and Hodgkin Reed-Sternberg-like cells. This is the first case report of a PD-L1-positive (PD-L1+) EBVMCU and the development of multiple EBV-driven B-LPDs in the setting of immunosenescence within a 32-month period.

DOI： 10.1111/pin.12738

Immune evasion-related extranodal large B-cell lymphoma: A report of six patients with neoplastic PD-L1-positive extranodal diffuse large B-cell lymphoma 査読有り

Suzuki, Y; Sakakibara, A; Shimada, K; Shimada, S; Ishikawa, E; Nakamura, S; Kato, S; Takahara, T; Asano, N; Satou, A; Kohno, K

PATHOLOGY INTERNATIONAL 69 巻 ( 1 ) 頁： 13 - 20 2019年1月

記述言語：英語出版者・発行元：Pathology International

We identified six patients with Epstein-Barr virus (EBV)-negative extranodal diffuse large B-cell lymphoma (DLBCL) and immunohistochemical expression of PD-L1 on their tumor cells by examining 283 DLBCL cases with the PD-L1 SP142 clone between 2015 and 2017. They consisted of two men and four women with a median age of 71 years, and were examined in an autopsy (n = 1) and biopsies from the adrenal gland (n = 2), skin (n = 1), pelvic cavity (n = 1), and kidney (n = 1). All showed a monomorphic population of large transformed B-cells leading to diagnoses of DLBCL with two intravascular large B-cell lymphoma (IVLBCL) and one de novo CD5+ type and were featured by an invariable immunephenotype: CD3-, CD20+, BCL-2+, and MUM1+. In addition, CD5 and CD10 were each detected in one case. All cases expressed PD-L1 on >10% to >90% of tumor cells, which was confirmed with two other PD-L1 antibodies (E1J2J and 28-8). Three untreated patients had a rapid, lethal clinical course within 7 months after diagnosis; while, the remaining three achieved complete remission after treatment and were alive at the last follow-up. We suggest immune evasion-related extranodal large B-cell lymphoma should be recognized beyond the currently identified entities of IVLBCL and de novo CD5+ DLBCL.

DOI： 10.1111/pin.12742

Case of primary central nervous system histiocytic sarcoma with prominent proliferation of histiocytic cells between the trabeculae of reactive glial cells 査読有り

Takahashi, E; Sakakibara, A; Tsuzuki, T; Nakamura, S

NEUROPATHOLOGY 38 巻 ( 6 ) 頁： 609 - 618 2018年12月

記述言語：英語出版者・発行元：Neuropathology

Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm that exhibits morphologic and immune-phenotype evidence of histiocytic differentiation. The disease most commonly involves the lymph nodes, gastrointestinal tract, skin, and soft tissue, as well as in the central nervous system (CNS) being relatively rare. Here we report a case of primary CNS HS with unusual histopathological characteristics. A 65-year-old woman presented with CNS HS in the left frontal lobe region, showing two distinct histological patterns. Approximately half of the lesion displayed histological characteristics typical of HS, including diffuse invasion of large round-to-ovoid pleomorphic cells, with mitotic figures (Ki-67 index: 30%) and coagulative necrotic foci. The other half exhibited prominent proliferation of histiocytic cells between the trabeculae of reactive glial cells, with rare mitotic figures (Ki-67 index: < 1%) and no necrotic foci. There were transitions between two morphologies. The HS tumor cells and the histiocytic cells between the trabeculae of reactive glial cells possessed nearly identical histomorphologic and immunophenotypic features, although the HS tumor cells showed a more pronounced degree of cytologic atypia and mitotic activity. To our knowledge, this is the first reported case of HS with prominent proliferation of the histiocytic cells between the trabeculae of reactive glial cells. Here we present the detailed histological, immunohistochemical, and molecular findings. Investigating cases of HS may provide insight into the pathogenesis of this disease.

DOI： 10.1111/neup.12510

Clinicopathological analysis of primary intestinal diffuse large B-cell lymphoma: Prognostic evaluation of CD5, PD-L1, and Epstein-Barr virus on tumor cells 査読有り

Ishikawa, E; Kato, S; Shimada, K; Tanaka, T; Suzuki, Y; Satou, A; Kohno, K; Sakakibara, A; Yamamura, T; Nakamura, M; Miyahara, R; Goto, H; Nakamura, S; Hirooka, Y

CANCER MEDICINE 7 巻 ( 12 ) 頁： 6051 - 6063 2018年12月

記述言語：英語出版者・発行元：Cancer Medicine

Background: Primary intestinal diffuse large B-cell lymphoma (iDLBCL) is rare. In this study, we investigated the clinicopathological features of this disease to further understand the prognostic value of CD5, programmed cell death ligand 1 (PD-L1), and Epstein-Barr virus (EBV) on tumor cells. Methods: Tumor specimens from 62 patients consecutively diagnosed with primary iDLBCL at a single institution were analyzed. Results: Our series consisted of EBV-positive (EBV + ) iDLBCL (n = 10), de novo CD5 + iDLBCL (n = 4), and DLBCL, not otherwise specified (DLBCL-NOS; n = 48). Notably, seven of 10 EBV + cases had treated lymphoma-associated (n = 4) or iatrogenic immunodeficiency (n = 3). Two of 10 EBV + cases expressed PD-L1 on tumor cells, whereas the remaining eight were positive for PD-L1 on microenvironment immune cells. Only one DLBCL-NOS case had neoplastic PD-L1 expression with a giant cell-rich appearance. Both EBV-harboring and PD-L1 expression on tumor cells, but not CD5, were associated with worse overall survival (OS) in iDLBCL patients receiving rituximab-containing chemotherapy (P = 0.0354, P = 0.0092, and P = 0.1097, respectively). Multivariate analysis identified PD-L1 positivity on tumor cells (P = 0.0106), PD-L1 negativity on microenvironment immune cells (P = 0.0193), and EBV positivity (P = 0.0324) as poor independent prognostic factors for OS. Among iDLBCL cases without any EBV association, CD5 positivity, or neoplastic PD-L1 expression, high PD-L1 expression (≥40%) on microenvironment immune cells predicted an extremely favorable outcome. Conclusion: EBV + iDLBCL mainly comprised immunodeficiency-associated patients, which may highlight the specificity of the intestine. PD-L1 expression on tumor cells or microenvironment immune cells was found to have an opposite prognostic impact in iDLBCL.

DOI： 10.1002/cam4.1875

Reappraisal of nodal Epstein-Barr Virus-negative cytotoxic T-cell lymphoma: Identification of indolent CD5<SUP>+</SUP> diseases 査読有り

Neoplastic PD-L1 expression on interdigitating dendritic cell sarcoma: A supplementary study of a case report 査読有り

Sakakibara, A; Takahashi, E; Ishikawa, E; Kohno, K; Asano, N; Nakamura, S

PATHOLOGY INTERNATIONAL 68 巻 ( 10 ) 頁： 577 - 578 2018年10月

Yamashita, D; Shimada, K; Takata, K; Miyata-Takata, T; Kohno, K; Satou, A; Sakakibara, A; Nakamura, S; Asano, N; Kato, S

CANCER SCIENCE 109 巻 ( 8 ) 頁： 2599 - 2610 2018年8月

記述言語：英語出版者・発行元：Cancer Science

Nodal cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein-Barr virus (EBV)-negative CTL to 48 patients with EBV-positive CTL. The two groups did not differ in histopathology, T-cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV-negative CTL less frequently showed hepatic involvement (P =.007), B symptoms (P =.020), hemophagocytosis (P =.024), and detectable CD4 (P =.002) and CD5 (P =.009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P =.002), CD5 expression (P =.002), and mixed morphology (P =.013), TCRαβ was not an independent predictor (P =.30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P =.007 vs P =.082) and Prognostic Index for PTCL (P =.020 vs P =.15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5+TCRαβ (n = 13), and CD5+ NK-cell type lacking TCR expression or clonal TCRγ rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P <.001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases.

DOI： 10.1111/cas.13652

A prognostic model, including the EBV status of tumor cells, for primary gastric diffuse large B-cell lymphoma in the rituximab era 査読有り

Ishikawa, E; Tanaka, T; Shimada, K; Kohno, K; Satou, A; EladI, AE; Sakakibara, A; Furukawa, K; Funasaka, K; Miyahara, R; Nakamura, M; Goto, H; Nakamura, S; Kato, S; Hirooka, Y

CANCER MEDICINE 7 巻 ( 7 ) 頁： 3510 - 3520 2018年7月

記述言語：英語出版者・発行元：Cancer Medicine

EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), often affects the gastrointestinal tract. However, the prognostic significance of EBV associated with primary gastric DLBCL (gDLBCL) has not been established. This retrospective study included 240 patients with primary gDLBCL, diagnosed between 1995 and 2015. Tumor specimens were analyzed with EBER in situ hybridization. In 25 (10%) cases, tumor cells harbored EBV. The EBV+ group more frequently exhibited programmed death-ligand 1 (PD-L1) expression in microenvironment immune cells, but not tumor cells, compared to the EBV− group (86% vs 43%, P =.006). Among 156 patients that received rituximab-containing chemotherapy, the EBV+ group had a significantly worse overall survival (OS) than the EBV− group (P =.0029). Multivariate analyses identified 3 independent adverse prognostic factors of OS: multiple gastric lesions (P =.002), EBER positivity (P =.003), and B symptoms (P =.018). These factors were combined to develop a gDLBCL prognostic (gDLP) model that significantly stratified the patients into 3 distinct risk groups (Scores: good = 0, intermediate = 1, and poor = 2/3, P <.0001) with 5-year OS rates of 100%, 81%, and 39%, respectively. Patients with EBV+ gDLBCL commonly exhibited microenvironmental PD-L1 expression and showed a significantly worse prognosis than subjects with EBV− gDLBCL. Our gDLP model, which included EBV+ tumor cells, provided good predictions of clinical outcome and may be useful for selecting patients in trials in the immune-oncology era.

DOI： 10.1002/cam4.1595

Comparison of Epstein-Barr virus-positive mucocutaneous ulcer associated with treated lymphoma or methotrexate in Japan 査読有り

Daroontum, T; Kohno, K; Eladl, AE; Satou, A; Sakakibara, A; Matsukage, S; Yakushiji, N; Ya-In, C; Nakamura, S; Asano, N; Kato, S

HISTOPATHOLOGY 72 巻 ( 7 ) 頁： 1115 - 1127 2018年6月

記述言語：英語出版者・発行元：Histopathology

Aims: The aim of the present study was to compare treated lymphoma-associated Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) and methotrexate (MTX)-associated EBVMCU. Methods and results: Of a series of 15 Japanese patients (11 women, four men; median age 74 years, range 35–84 years), seven received MTX for the treatment of autoimmune disease and eight developed EBVMCU after treatment of malignant lymphoma [diffuse large B-cell lymphoma (n = 4) without EBV association, adult T-cell leukaemia/lymphoma (n = 2), angioimmunoblastic T-cell lymphoma (n = 1), and follicular lymphoma (n = 1)]. Ulcers were observed in the oral cavity (n = 11), gastrointestinal tract (n = 2), and skin (n = 2). All were histologically characterised by a mixture of EBV-positive large B-cell proliferation and Hodgkin/Reed–Sternberg-like cells on a polymorphous background. A total of 46% (6/13) had monoclonal immunoglobulin heavy chain gene rearrangement, but none had clonal T-cell receptor gene rearrangement. Spontaneous regression occurred in 13 of 15 cases (87%); the other two cases (13%) achieved complete remission after treatment. Of two patients in the treated lymphoma-associated subgroup, one developed multiple new ulcerative lesions on previously unaffected skin, and the other had a relapse of EBVMCU in the oral cavity. No significant clinicopathological differences were found between the subgroups. Notably, none of the patients died from EBVMCU. However, the treated lymphoma-associated subgroup had lower overall survival (P = 0.004) and a shorter follow-up period (P = 0.003) than the MTX-associated subgroup, owing to death from non-associated causes. Conclusions: Treated lymphoma-associated EBVMCU, which is an indolent and self-limited condition, must be recognised to avoid misdiagnosing it as a relapse of malignant lymphoma during treatment.

DOI： 10.1111/his.13464

Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells 査読有り

Sakakibara, A; Kohno, K; Eladl, AE; Klaisuwan, T; Ishikawa, E; Suzuki, Y; Shimada, S; Nakaguro, M; Shimoyama, Y; Takahara, T; Kato, S; Asano, N; Nakamura, S; Satou, A

HISTOPATHOLOGY 72 巻 ( 7 ) 頁： 1156 - 1163 2018年6月

記述言語：英語出版者・発行元：Histopathology

Aims: The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumour cells escape from immune control. PD-L1 immunohistochemistry is a useful predictor of immunotherapy response, but is still not used widely in the diagnostic setting. Here we describe results using PD-L1 immunohistochemistry during routine diagnostics in lymphoma. Methods and results: Ninety-one lymphoproliferative disease cases sharing tumour and non-malignant Hodgkin–Reed-Sternberg (HRS)-like cells with and without Epstein–Barr virus (EBV) association were investigated by immunohistochemistry for PD-L1 (clone SP142). PD-L1 expression was present in more than 5% of tumour or non-malignant HRS-like cells in 100% of EBV+ classical (C) Hodgkin lymphoma (HL) (n = 10) and EBV-negative nodular sclerosis CHL (n = 8); 40% of EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL–NOS) (n = 20); and 4% of nodal peripheral T cell lymphoma of follicular helper T cell type (PTCL-TFH) (n = 22). In contrast, nodular lymphocyte-predominant HL (n = 4), lymphocyte-rich CHL (n = 6), EBV+ hyperplasia (n = 8), plasmablastic lymphoma (n = 3) and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 5) seldom exhibited PD-L1 in their large cells. Assessing PD-L1 positivity in tumour and non-malignant large cells was helpful in differentiating between CHL versus nodal PTCL–TFH (P < 0.0001) or EBV+ DLBCL–NOS (P = 0.0052) and between EBV+ DLBCL–NOS versus nodal PTCL-TFH (P = 0.0052), with PD-L1 expression indicating the first diagnosis in each of those sets. Conclusion: Immunohistochemical evaluation of PD-L1 expression in tumour and non-malignant HRS-like large cells may be useful for assessing either immune escape or immunodeficiency in their pathogenesis.

DOI： 10.1111/his.13475

Anaplastic variant of diffuse large B-cell lymphoma with hallmark cell appearance: Two cases highlighting a broad diversity in the diagnostics 査読有り

Sakakibara, A; Kohno, K; Kuroda, N; Yorita, K; Megahed, NA; Eladl, AE; Daroontum, T; Ishikawa, E; Suzuki, Y; Shimada, S; Nakaguro, M; Shimoyama, Y; Satou, A; Kato, S; Yatabe, Y; Asano, N; Nakamura, S

PATHOLOGY INTERNATIONAL 68 巻 ( 4 ) 頁： 251 - 255 2018年4月

記述言語：英語出版者・発行元：Pathology International

The anaplastic variant of diffuse large B-cell lymphoma (A-DLBCL) is morphologically defined but remains an enigmatic disease in its clinicopathologic distinctiveness. Here, we report two cases involving Japanese women aged 59 years, both with A-DLBCL with the hallmark cell appearance and both indistinguishable from common and giant cell-rich patterns, respectively, of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. Case 1 was immunohistochemically positive for CD20, CD79a and OCT-2 but not for the other pan–B-cell markers, CD30 and ALK. Case 2 showed CD20 and CD30 positivity for 50% and 20% of tumor cells in addition to strong expression of p53 and MYC. Both were positive for fascin without Epstein–Barr virus association. Our cases provide additional support for the earlier reports that A-DLBCL exhibits clinicopathologic features distinct from ordinal diffuse large B-cell lymphoma (DLBCL), and documented its broader morphologic diversity than previously recognized. They also shed light on the unique feature of absent expression of pan–B-cell markers except for CD20 and CD79a, suggesting that A-DLBCL may biologically mimic a gray zone or intermediate lymphoma between DLBCL and classic Hodgkin lymphoma.

DOI： 10.1111/pin.12653

Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression.

Sakakibara A, Inagaki Y, Imaoka E, Ishikawa E, Shimada S, Shimada K, Suzuki Y, Nakamura S, Satou A, Kohno K

Journal of clinical and experimental hematopathology : JCEH 58 巻 ( 1 ) 頁： 32 - 35 2018年3月

記述言語：英語出版者・発行元：日本リンパ網内系学会

<p>Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically distinctive entity characterized by the almost exclusive growth of large cells within the lumen of blood vessels in particular capillaries. Reports of this peculiar disease, do not commonly address the PD-L1 expression on IVLBCL tumor cells. Here, we describe a 51-year-old Japanese woman who presented with rapidly progressive cognitive decline and higher brain dysfunction. CT scan and MRI revealed multiple ischemic foci in the cerebral hemispheres, ground-glass opacity in the lungs, and splenomegaly. Random skin biopsy for IVLBCL diagnosis yielded negative results. The patient experienced a rapidly deteriorating clinical course with no treatment, and died from the disease after 3 months of hospitalization. Post-mortem examination revealed systemic intravascular plugging of lymphoma cells, without mass lesions in the central nervous system or in visceral organs such as the lungs, liver, pituitary gland, ovaries, and uterus. The tumor cells were positive for CD10, CD20, BCL2, BCL6, and MUM1, but not other lineage-specific markers. Notably, the tumor cells showed strong PD-L1 expression. Our case was diagnosed as IVLBCL with neoplastic PD-L1 expression. These findings suggest that PD-L1 is associated with immune evasion of IVLBCL and may play a role in the pathogenesis and peculiar biological behavior of this unique disease. Additionally, PD-L1 may represent a possible therapeutic target for immune check-point inhibitors.</p>

DOI： 10.3960/jslrt.17037