Akira Satou

T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases.

Among Epstein-Barr virus (EBV)-positive cytotoxic T/NK-cell lymphoma, there are only a few reports on the clinicopathologic features of patients with primary nodal presentation (nodal EBV+ cytotoxic T-cell lymphoma [CTL]). Here, we compared the clinicopathologic profiles of 39 patients with nodal EBV+ CTL with those of 27 cases of “extranasal” NK/T-cell lymphoma of nasal type (ENKTL), especially addressing their T-cell receptor (TCR) phenotype. Histologically, 22 of 39 nodal EBV+ CTL cases (56%) were unique in having centroblastoid appearance, which was contrasted with the lower incidence of this feature in ENKTL (15%, P=0.001). In contrast, pleomorphic appearance was more frequently seen in ENKTL than in nodal EBV+ CTL (67% vs. 23%, P=0.001). Thirty-three of 39 nodal EBV+ CTL cases (85%) were of T-cell lineage on the basis of TCR expression and/or TCR&ggr; gene rearrangement; in detail, 18 cases (46%) were TCR&bgr; positive (&agr;&bgr; T), 5 (13%) were TCR&ggr; and/or &dgr; positive (&ggr;&dgr; T), and 10 (26%) were TCR-silent type with clonal TCR&ggr; gene rearrangement but no expression of TCR&bgr;, &ggr;, or &dgr;. These results were clearly contrasted by a lower incidence of T-cell lineage in ENKTL (7 cases, 26%, P<0.001). Notably, the survival time of the 5 nodal lymphoma patients with &ggr;&dgr; T-cell phenotype was within 3 months, which was inferior to those of &agr;&bgr; T and TCR-silent types (P=0.003), and 3 of those with available clinical information were all found to be associated with autoimmune diseases. These data suggest that nodal EBV+ CTL is distinct from ENKTL.

IgG4-related neuropathy: a case report.

IMPORTANCE The newly recognized entity IgG4-related disease (IgG4-RD) is characterized by an elevated IgG4 serum concentration and tissue infiltration by IgG4-positive plasma cells. We describe, for the first time, the clinical features and nerve biopsy findings of a patient with IgG4-RD who presented with neuropathy in the extremities. OBSERVATIONS A 55-year-old man had histopathologically defined IgG4-RD that manifested as sensory-motor neuropathy. The neuropathic features were multiple mononeuropathies with electrophysiological findings suggestive of axonal neuropathy. Marked thickening with abundant collagen fibers and infiltration of IgG4-positive plasma cells were observed in the epineurium of the biopsied sural nerve. A moderate degree of myelinated fiber loss without evidence of segmental demyelination was present, whereas necrotizing vasculitis was not found. Oral prednisolone therapy ameliorated the neuropathic symptoms. CONCLUSIONS AND RELEVANCE This case of IgG4-RD presented as sensory-motor neuropathy with pain and sclerosis of the skin in the extremities. The differential diagnosis of neuropathy should include IgG4-RD.

Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells.

Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.

Frequent MYD88 L265P and CD79B Mutations in Primary Breast Diffuse Large B-Cell Lymphoma.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising <3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NF&kgr;B pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at &Dgr;Ct⩽1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi’s algorithm, 16/27 (59.3%) demonstrated an ABC-like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis.

Epstein-Barr Virus (EBV)-positive Sporadic Burkitt Lymphoma An Age-related Lymphoproliferative Disorder?

Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV+) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV+ sBL, we compared the clinicopathologic characteristics of 33 cases of EBV+ and 117 cases of EBV-negative (EBV−) sBL in Japan. EBV+ sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV+ group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV+ group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV+ sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV+ sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV+ sBL might be different from those of EBV− sBL. Our results demonstrate that EBV+ sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV− sBL.

Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL)

Epstein–Barr virus‐positive (EBV+) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patients background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL.

Epstein-Barr virus–positive mucocutaneous ulcer arising in a post–hematopoietic cell transplant patient followed by polymorphic posttransplant lymphoproliferative disorder and cytomegalovirus colitis

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a newly described entity occurring in elderly or iatrogenically immunocompromised patients. We describe a case of EBVMCU arising in a post-hematopoietic cell transplant patient and followed by EBV-positive polymorphic posttransplant lymphoproliferative disorder (EBV+ polymorphic PTLD). The patient, a 52-year-old woman, received chemotherapy and autologous peripheral blood stem cell transplantation for relapsed diffuse large B-cell lymphoma (DLBCL). She achieved complete remission and was followed up in an outpatient clinic after discharge. One year later, EBVMCU appeared in the tongue and exhibited spontaneous regression. Six months after the regression of the EBVMCU, she had EBV+ polymorphic PTLD, analogous to EBV+ polymorphic DLBCL. The therapy for PTLD was not effective, and the patient finally died of disease progression. This was the first case of EBVMCU characterized by both an association with autologous peripheral blood stem cell transplantation and subsequent emergence of malignant lymphoma in a patient with relapsed DLBCL.

Clinicopathologic Spectrum of Gastrointestinal T-cell Lymphoma: Reappraisal Based on T-cell Receptor Immunophenotypes.

The differential diagnosis of primary gastrointestinal EBV− T-cell lymphoma (GITCL) includes enteropathy-associated T-cell lymphoma (EATL), peripheral T-cell lymphoma, not otherwise specified, adult T-cell leukemia/lymphoma, and anaplastic large cell lymphoma. Type II EATL is considered to be a tumor of intraepithelial lymphocytes. However, the evaluation of intraepithelial lymphocytosis by biopsy specimens is challenging, which poses a diagnostic problem between the EATL and peripheral T-cell lymphoma, not otherwise specified. This situation requested us to establish a pragmatic diagnostic approach for the classification of GITCL. We identified 42 cases of GITCL and analyzed clinicopathologic features, especially addressing their T-cell receptor (TCR) phenotype. Nine (21%) of 42 GITCL cases were positive for TCR&ggr; protein expression. Among these TCR&ggr;+ cases, TCR&bgr; expression or not was detected in 5 and 4, respectively, but resulted in no further clinicopathologic differences. TCR&bgr; positivity without TCR&ggr; expression (&bgr;+&ggr;−) was seen in 9 GITCL patients (21%). Twenty-four patients (57%) were negative for TCR&bgr; and &ggr; expression (&bgr;−&ggr;−). Compared with TCR&bgr;+&ggr;− or &bgr;−&ggr;− type, TCR&ggr;+ cases were characterized by exclusive involvement of intestinal sites (100% vs. 11%, P<0.001; 100% vs. 58%, P=0.032, respectively), but not of stomach (0% vs. 78%, P=0.002; 0% vs. 38%, P=0.039, respectively). Notably, TCR&ggr; positivity was an independent unfavorable prognostic factor among our GITCL patients (P<0.001). Considering our results, TCR&ggr;+ GITCL, that is, intestinal &ggr;&dgr; T-cell lymphoma, appears to constitute a distinct disease entity.

FoxP3-positive T cell lymphoma arising in non-HTLV1 carrier: clinicopathological analysis of 11 cases of PTCL-NOS and 2 cases of mycosis fungoides.

Forkhead box protein 3‐positive (FoxP3+) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV‐1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics.

Clinicopathological analysis of 46 cases with CD4+ and/or CD56+ immature haematolymphoid malignancy: reappraisal of blastic plasmacytoid dendritic cell and related neoplasms

In this study, we aimed to investigate the clinicopathological features of CD4+ and/or CD56+ immature haematolymphoid malignancy (iHLM), including blastic plasmacytoid dendritic cell neoplasm (BPDCN).