Ayako Sakakibara

Distribution of nestin and other stem cell‐related molecules in developing and diseased human spinal cord

In mammalian spinal cords, no neurogenesis has been observed after initial development. However developed mammalian spinal cords seemingly contain neural stem cells (NSC), which can give rise to neurons and glial cells when they are placed in appropriate environments. The purpose of the present paper was to investigate the developing, developed, and diseased human spinal cord to see which cell types have an immunophenotype similar to NSC. In 12 specimens from preterm neonates and term infants up to 14 months old, nestin was expressed in cells that extended fibrous processes and were located around the midline in the ependymal layer. In all the preterm neonates, Musashi‐1 and glial fibrillary acidic protein (GFAP) were also expressed in this subpopulation, whereas Lewis X was detected in a less restricted subpopulation. Nestin expression by these cells was not detected in most adult spinal cords, but was observed in three spinal cords from 13 amyotrophic lateral sclerosis patients and eight of 14 spinal cords involved by the tumor. The present observations suggest that during gestation a subpopulation of cells in the ependymal layer remains undifferentiated as potential NSC/neural progenitor cells, and becomes unidentifiable in early infancy. These cells, however, appear in response to disease conditions, especially tumor involvement.

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

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.

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

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.

Neoplastic PD-L1 expression on interdigitating dendritic cell sarcoma: A supplementary study of a case report: Letter to the Editor

To the Editor: Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm, accounting for slightly more than 100 cases reported in the English literature, with the largest series to date consisting of four cases. The introduction of programmed death 1 (PD1)/PD1 ligand (PD-L1) pathway inhibitors have revolutionized cancer treatment with impressive responses in a broad variety of tumor types. Much interest now focuses on tumor cell (neoplastic) PD-L1 expression in lymphoid malignancies, exemplified by classic Hodgkin lymphoma (CHL). One of the authors (SN) reported this rare disease as a single case report in 1988, the details of which were documented in a series of sequential studies. Here, we show immunohistochemical expression of PD-L1 on the tumor cells of our IDCS patient using anti-PD-L1 antibodies (SP142, 1:50, Spring Bioscience, Pleasanton, CA, USA; E1J2J, 1:50, Cell Signaling Technology, Danvers, MA, USA; and 28-8, 1:50, Abcam, Cambridge, MA, USA) (Fig. 1). Briefly, this 58-year-old male patient presented with a left neck mass in 1982. Our preferred diagnosis was malignant lymphoma, unclassifiable, but the patient posed a challenge of a differential diagnosis of CHL. The tumor recurred twice in the jejunum with involvement of the mesenteric lymph nodes despite CHOP treatment. These recurrent lesions were excised twice in 1986. The patient died of pneumonia in 1990, 101 months after the original biopsy. Autopsy revealed no residual tumor. The tumor cells were positive for CD4, CD68, CD163 (Fig. 1b), and S100 protein, but not for CD1a, CD34, CD207/ langerin, or markers of follicular dendritic cells, or B-cell or other T-cell associated antigens. Notably, our case exhibited strong immunohistochemical expression of PD-L1 on the membrane and/or in the cytoplasm of >80% of the tumor cells with all three anti-PD-L1 clone antibodies (Fig. 1c–f). To the best of our knowledge, this is the first report examining this issue in the English literature. The background T-lymphocytes were largely occupied by Fox-P3þ type, but rarely PD-1þ type, the pattern of which topologically resembled the pattern documented as governing antitumor immunity in CHL. Currently, there is no established standard for the treatment of IDCS patients. This disease also has the uncommon clinical behavior of extranodal localization or involvement of the liver (27%), spleen (18%), skin (15%), lung (12%), or small intestine (11%). We supplementarily described our case for its biological interest in neoplastic PD-L1 expression, which not only represents an attractive therapeutic target in this era of immuno-oncology, but may be associated with peculiar clinical behavior, preferably affecting the unusual extranodal sites uncommon in CHL. On the other hand, our study indicated that a diagnosis of IDCS is still challenging to pathologists because of its superficial resemblance to CHL with neoplastic PD-L1 expression. These issues should be clarified in the future.

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

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.

Case of primary central nervous system histiocytic sarcoma with prominent proliferation of histiocytic cells between the trabeculae of reactive glial cells: CNS HS with histiocytic proliferation

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.

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

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.

Reappraisal of nodal Epstein-Barr Virus-negative cytotoxic T-cell lymphoma: Identification of indolent CD5+ diseases

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.

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

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.