[Spontaneous regression of HIV-associated EBV-positive mucocutaneous ulcer due to immune reconstruction with antiretroviral therapy].

A 24-year-old man was found to have an ileocecal ulcer by colonoscopy. A pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) with diffuse positive reaction of Epstein-Barr encoding region (EBER) by in situ hybridization was made based on analysis of the specimen. Acquired immunodeficiency syndrome (AIDS) complicated by pneumocystis jirovecii pneumonia was also diagnosed. As no other significant lymphomatous lesions were identified by further examination, a clinical diagnosis of EBV-positive mucocutaneous ulcer (EBVMCU) was made. Rather than performing systemic chemotherapy, the lesion was closely monitored and antiretroviral therapy (ART) for AIDS was started with the hope of treating the lesion through immune reconstitution. The lesion had completely disappeared by day 79 after starting ART, and has not recurred for over 3 years. EBVMCU is known to develop secondary to various immunosuppressive states including AIDS. Here we report a rare case of EBVMCU detected at diagnosis of AIDS that entered complete remission after immune reconstitution by ART.

The clinical impact of the ratio of C-reactive protein to albumin (CAR) in patients with acute- and lymphoma-type adult T-cell leukemia-lymphoma (ATL).

Recently, the ratio of C-reactive protein to albumin (CAR) is used as an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in solid tumors and hematological malignancy. However, no studies of the CAR have been performed in patients with adult T-cell leukemia-lymphoma (ATL). We retrospectively analyzed the clinical features and outcomes in 68 newly diagnosed acute- and lymphoma-type ATL [(acute-(n=42) or lymphoma-type (n=26)] patients in Miyazaki Prefecture from 2013 to 2017. Furthermore, we investigated correlations between pretreatment CAR levels and clinical features. The median age was 67 years (range, 44 - 87). Patients were initially treated by either palliative therapy (n=14) or chemotherapy [n=54; CHOP therapy (n=37)/ VCAP-AMP-VECP therapy (n=17)], and showed median survival durations of 0.5 months and 7.4 months, respectively. The factors affecting OS by multivariate analysis were age, BUN, and CAR. Importantly, we revealed that the high CAR group (optimal cut-off point; 0.553) was a significant indicator of worse OS by multivariate analysis (p< 0.001, HR; 5.46). The median survival of patients with a CAR< 0.553 was 8.37 months, while patients with a CAR>0.553 had a median survival of 3.94 months. The different clinical features between high CAR and low CAR groups were hypoproteinemia and the implementation of chemotherapy. Furthermore, in the chemotherapy group, but not the palliative therapy group, CAR was a significant prognostic marker. Our study indicated that CAR may be a new simple and significant independent prognostic marker in acute- and lymphoma-type ATL patients.

Adult Nodal Burkitt Lymphoma Forming Nodular Architectures.

In this report, we discuss a case of nodal Burkitt lymphoma seen in a 60-year-old Japanese male patient. Microscopic features of the biopsied 30 mm-sized cervical lymph node revealed nodular architectures with starry sky appearance surrounded by small mantle zone B-lymphocytes. Immunohistochemical and molecular studies demonstrated typical features of sporadic Burkitt lymphoma: the atypical cells were positive for CD20, CD79a, CD10, CD23, HLA-DR, bcl-6, PAX5, c-myc, and cytoplasmic IgM, but negative for CD3, CD5, CD15, CD30, CD34, TdT, bcl-2, and MUM1. The mantle zone B-cells were clearly positive for bcl-2 and IgD. In situhybridization (ISH) analysis for immunoglobulin light chains showed kappa-type monoclonality. A few nuclei were labeled for Epstein-Barr virus-encoded small nuclear RNA (EBER). Ki-67 labeling index was nearly 100%. Within the nodule, CD21, CD23, and CD35-positive follicular dendritic cells were scattered with a small number of CD3/CD5-positive small T-lymphocytes, indicating that the nodular architecture represented follicular colonization of Burkitt lymphoma cells. Karyotypic analysis revealed t(8;14)(q24;q32), and IGH-MYC fluorescence in situ hybridization (FISH) demonstrated IGH-MYC fusion signals. The presentation of follicular colonization was quite unique in Burkitt lymphoma in the present case. Differential diagnosis is also discussed.

Chromosomal defects and survival in patients with adult T-cell leukemia/lymphoma after allogeneic HSCT.

Adult T-cell leukemia/lymphoma (ATL) cells frequently exhibit chromosomal abnormalities, including numerical aberrations and structural defects. However, no studies have examined the correlation between these abnormalities and survival in patients with ATL after allogeneic HSCT (allo-HSCT). In this study, 300 patients with ATL (median age, 55 years; range, 24-74) who were registered in a Japanese nationwide registry database were analyzed. The majority (n = 183) had acute ATL. Specimens for chromosomal analysis were collected from bone marrow (n = 166), lymph nodes (n = 86), peripheral blood (n = 41), and other locations (n = 7). In survival analyses, breakpoints at 2q (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.12-2.38; P = .012) and 5q (HR, 2.18; 95% CI, 1.25-3.80; P = .006) were significantly poor prognostic factors for overall survival (OS). In terms of ATL-related death, loss of chromosome 14 and breakpoints at 3p, 1q, 5q, and 6q were extracted as significantly poor prognostic factors. Moreover, complex karyotypes were associated with ATL-related death. This study of the survival impact of chromosomal abnormalities in patients with ATL after allo-HSCT demonstrated that several structural breakpoints were independent risk factors for OS and ATL-related death.

Identification of a novel CCDC22 mutation in a patient with severe Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia.

Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein-Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation of coiled-coil domain-containing 22 (CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified. High EBV viral load was detected in NK cells fractionation by qPCR. The initial diagnosis was EBV-related hemophagocytic lymphohistiocytosis (EBV-HLH). A combination of immunosuppressive drugs and chemotherapy was administered, but was unsuccessful in controlling the disease. Therefore, he was treated with HLA-matched related allogeneic hematopoietic stem cell transplantation. However, his condition deteriorated within 30 days, resulting in fatal outcome. Autopsy revealed many EBV-infected NK cells infiltrating major organs, consistent with ANKL. Furthermore, whole-exome sequencing identified a novel missense mutation of the CCDC22 gene (c.112G>A, p.V38M), responsible for X-linked intellectual disability (XLID). CCDC22 has been shown to play a role in NF-κB activation. Our case suggests that CCDC22 mutation might be implicated in pathogenesis of EBV-HLH and NK-cell neoplasms as well as XLID via possibly affecting NF-κB signaling.

Methotrexate-associated lymphoproliferative disorders with angioimmunoblastic T-cell lymphoma-like features accompanied by gamma-heavy chain disease in a patient with rheumatoid arthritis.

Although gamma heavy chain disease (γ-HCD) lesions occasionally morphologically resemble angioimmunoblastic T-cell lymphoma (AITL), no association has been described in detail due to the rarity of the disease. In this report, we present a rare manifestation of methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) with AITL-like features accompanied by γ-HCD in a 75-year-old man with rheumatoid arthritis (RA). A biopsy specimen was evaluated using immunohistochemistry, clonal analyses of immunoglobulin VH and T-cell receptor γ gene rearrangements by polymerase chain reaction, and Sanger sequencing for confirmation of the structure of deleted γ-HCD clones. The histological features characterized by proliferation of CD4- and PD-1-positive medium-sized T cells and arborizing high endothelial venules together with numbers of small lymphocytes, eosinophils, plasma cells, and histiocytes in the background mimicked those of AITL, but did not completely fulfill the diagnostic criteria. Clonal analysis demonstrated that the specimen contained multiple LPDs of both B-cell and T-cell lineages. Sequence analysis confirmed the co-existence of a clone responsible for production of the abnormal heavy chain. This report provides new insights into the pathology of γ-HCD. Multiple host-derived factors (e.g., RA and/or use of MTX) may be responsible for the occurrence of LPDs of multiple lineages within a single lymph node.

[Splenic diffuse red pulp small B-cell lymphoma diagnosed by splenectomy initially mimicking hairy cell leukemia-Japanese variant].

A 62-year-old man presented to the hospital with thrombocytopenia, and splenomegaly was detected. His blood films prepared by natural air drying revealed medium-sized lymphocytes with unevenly distributed large and small villous projections. The cytoplasm was basophilic, nuclei were oval with clumped chromatin, and nucleoli were absent in most cells. Immune phenotypes CD19+, CD20+, CD11c+, FMC7+, IgM+, and Igκ+ were detected. TRAP stain appeared negative, IgH JH chain genes were monoclonally rearranged, and BRAF V600E mutation was not detected. On the basis of these findings, hairy cell leukemia-Japanese variant (HCL-JV) was strongly suspected. The patient was followed up for >4 years without treatment. However, because thrombocytopenia and splenomegaly gradually progressed, splenectomy was performed. Microscopic examination confirmed that the splenic white pulp was atrophic. Moreover, infiltrates comprising small-to-medium-sized atypical lymphocytes with inconspicuous nucleoli were predominantly detected in the congested red pulp. On the basis of these results and immune histochemical findings, the patient was diagnosed with splenic diffuse red pulp small B-cell lymphoma (SDRPL). Here we discussed whether the aforementioned diseases (HCL-JV and SDRPL) are the same; however, further accumulation of cases is essential to draw a definite conclusion.

Toxic epidermal necrolysis in a child 6 months post-hematopoietic stem cell transplantation.

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B-cell acute lymphoblastic leukemia (pre-B-ALL) in second complete remission. Although we did not evaluate the T-cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.

Splenic marginal zone lymphoma uncovered after a 10-year follow up as anemia of unknown cause.

A 75-year-old man was referred to our hospital for evaluation of persistent anemia. Despite repeated diagnostic tests, including bone marrow aspiration, the cause of his anemia remained unknown. On each occasion, computed tomography had revealed neither swollen lymph nodes nor splenomegaly. After a 10-year follow-up period, he was admitted with general fatigue and had developed splenomegaly as well as the anemia. Bone marrow biopsy revealed increased abnormal lymphocytes with short villi that were positive for CD11c, CD19, CD20, and kappa chain, but not for CD5, CD10, CD23, or cyclin D1, according to flow cytometry. The bone marrow biopsy sample showed nodular proliferation of small to medium-sized abnormal lymphocytes. Based on these findings, the patient was diagnosed as having splenic marginal zone lymphoma, a rare indolent B-cell neoplasm. Although his splenomegaly diminished after eight cycles of weekly rituximab monotherapy, the anemia did not improve, and abnormal lymphocytes remained detectable in his bone marrow. The patient was then treated with bendamustine monotherapy for six cycles, after which the anemia resolved, and he has since been in good condition. Although rare, it is important to consider splenic marginal zone lymphoma during the differential diagnosis of patients with a long history of anemia of unknown cause.

An Epstein-Barr virus susceptible immature T-cell line, WILL4, established from a patient with T-lymphoblastic lymphoma bearing CD21 and a clonal EBV genome.

We managed a patient with an Epstein-Barr virus-associated T-cell lymphoblastic lymphoma. Mediastinal tumor cells at initial admission were positive for CD4, CD8, and TdT. Interestingly, a lymph node at necropsy was compatible for a CD4-positive peripheral T-cell lymphoma without CD8 and TdT expression, suggesting a different phenotype from the mediastinal tumor. Tumor cells in pleural effusion continued to proliferate in in vitro and were designated as WILL4. WILL4 cells were positive for CD3, CD4, CD8, CD21, T-cell receptor (TcR) αß, and TdT, indicating a similar phenotype to thymocytes. Southern blot analyses showed that the pleural tumor and WILL4 cells shared a TcR gene rearrangement, and that both contained a clonal EBV genome in an episomal form. RT-PCR showed that EBNA1 and LMP1 were expressed in the fresh tumor and WILL4 cells. Southern blot analyses revealed that WILL4 cells were susceptible to EBV infection in vitro using B95-8 supernatant. Anti-CD21 antibody inhibited in vitro infection of EBV, suggesting that CD21 plays a role in EBV infection into WILL4 cells. In vitro infection of EBV did not affect latent gene expression in WILL4 cells. WILL4 is a useful tool for analyzing the roles of EBV in onocogenesis in immature T-lymphoid malignancies.

Epstein-Barr Viral Load is Associated to Response in AIDS-Related Lymphomas.

AIDS-related lymphoma (ARL) development is associated to immunodeficiency state with proliferation of B-cells driven by HIV itself and EBV infection. However, Epstein-Barr DNA is not detected in malignant cells of all ARL subtypes. A prospective and controlled study to analyze EBV viral load (VL) in plasma and peripheral blood mononuclear cells (PBMC) of ARL patients was performed to analyze if Epstein-Barr VL could be related to response in these patients. Fifteen patients with ARL were included in this study with measurement of EBV VL at three different periods of time: at lymphoma diagnosis, upon completion of chemotherapy, and 3 months after. Two control groups composed by HIV-negative and HIV-positive patients were also evaluated for EBV VL comparison. In situ hybridization for EBER was performed on diagnostic samples of all ARL patients. Median EBV VL in PBMC and plasma had a significant decrease (p = 0.022 and p = 0.003, respectively) after ARL treatment. EBER was positive in 7 (46.7 %) cases. Median EBV VL in PBMC before lymphoma treatment in patients positive for EBER was significantly higher compared to EBER negative cases (p = 0.041). Reduction of EBV viral load during treatment of lymphoma could be predictive of response. EBER expression was associated to advanced stages of disease and worse immune status. Our study suggests that measurement of EBV VL during ARL treatment could be used as a marker for response, but further studies are needed to validate this association.

Pediatric subcutaneous panniculitis-like T-cell lymphoma with favorable result by immunosuppressive therapy: a report of two cases.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare type of skin lymphoma. Histopathology mimicking a lobular panniculitis makes it difficult to distinguish SPTL from benign autoimmune disease. We present cases of a 10-year-old female and an 11-year-old male with SPTL showing recurrent panniculitis and systemic manifestations. Initially, antibiotics and steroids were administered to treat infectious disease and benign panniculitis. However, they experienced recurrent fever and erythema nodosum. Additional immunohistochemistry and T-cell receptor (TCR) gene rearrangement analyses were performed, enabling the establishment of an SPTL diagnosis. The affected patients were given immunosuppressive therapy with favorable results.

Improved treatment results of children with B-cell non-Hodgkin lymphoma: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group B-NHL03 study.

BACKGROUND: Previous Japanese studies of childhood B-cell non-Hodgkin lymphoma (B-NHL) have shown a favorable outcome, though the study size was too small to effectively assess the efficacy and safety of treatment for childhood B-NHL. PROCEDURE: We performed a nation-wide prospective B-NHL03 study to assess the efficacy and safety of short-pulse intensive chemotherapy for children with B-NHL. They were stratified into four treatment groups according to disease stage, tumor resectability and bone marrow/CNS involvement: Group 1 with all resected stage I/II, Group 2 with non-resected stage I/II, Group 3 with stage III & CNS-negative stage IV, and Group 4 with CNS-positive stage IV & Burkitt leukemia. Treatment duration was 2 courses for Group 1, 4 courses for Group 2, and 6 courses for Groups 3 and 4, respectively. CNS irradiation was omitted in all patients. RESULTS: The follow-up time ranged from 0.8 to 88 months, with a median of being 45 months. For 321 patients analyzed in this study, overall survival and event-free survival (EFS) at 4 years was 92.7% and 87.4%, respectively. The 4-year EFS according to treatment group were 94% for Group 1 (n = 17), 98% for Group 2 (n = 103), 84% for Group 3 (n = 111), and 78% for Group 4 (n = 90). There was no significant difference in outcome by histology. Therapy-related death occurred in three patients in remission. CONCLUSIONS: Our nationwide large-scale study resulted in a cure rate above 90% with <1% toxic death in childhood B-NHL.

Meeting report on the possible proposal of an extranodal primary cutaneous variant in the lymphoma type of adult T-cell leukemia-lymphoma.

Based on the advances in research on the clinicopathophysiology of adult T-cell leukemia-lymphoma (ATL), Japanese researchers collected and evaluated cases of smoldering ATL exhibiting primary cutaneous manifestation but showing poor prognosis. Macroscopic findings of skin eruptions were categorized into the patch, plaque, multipapular, nodulotumoral, erythrodermic and purpuric types, as previously reported. Pathological findings were divided into low or high grade based on epidermotropism, tumor cell size and perivascular infiltration. Eight eligible cases were evaluated among 14 collected cases. Macroscopic findings were nodulotumoral in six cases, a subcutaneous tumor in one case and plaque in one case, and the number and size were heterogeneous in each case. Pathological findings of all eight cases were T-cell lymphoma, high-grade type (pleomorphic, medium or large size), with prominent perivascular infiltration and scant epidermotropism. To diagnose such cases as the "lymphoma type of ATL, extranodal primary cutaneous variant", it is essential to examine each case carefully, including cutaneous lesions at onset, lymph nodes and other organ involvement using computed tomography (CT) and/or positron emission tomography/CT, as well as the percentage of abnormal lymphocytes in peripheral blood. Based on the results of an ongoing nationwide survey on ATL, ATL with cutaneous lesions will be analyzed to investigate the incidence and prognosis of the so-called "lymphoma type of ATL, extranodal primary cutaneous variant".

Influence of splenectomy in patients with liver cirrhosis and hypersplenism.

AIM: Splenectomy improves hypersplenic thrombocytopenia in cirrhotic patients with hypersplenism. However, the long-term influence of splenectomy has not been clarified. We examined whether splenectomy improved liver fibrosis and caused immunological changes. METHODS: We collected liver and spleen specimens and peripheral blood (PB) from 26 patients with hepatitis C virus-related liver cirrhosis. An immunohistochemical examination of CD4, CD8, forkhead box P3, granzyme B and transforming growth factor-ß1, and Masson-trichrome stain were performed in spleen and liver tissues and in seven cases of follow-up liver biopsy sections obtained after splenectomy. We obtained PB before and at various intervals after splenectomy. We also examined the ratio of CD4(+) and CD8(+) lymphocytes in PB using flow cytometry. RESULTS: We observed improvements in liver fibrosis in four biopsy specimens obtained after splenectomy, in which fibrotic areas significantly decreased from 19.5% to 8.2% (P < 0.05). Increases were also observed in the ratio of CD8(+) cells in PB after splenectomy, which resulted in a significant decrease in the CD4(+) /CD8(+) ratio (P < 0.001). The carcinogenic rate in patients with a CD4(+) : CD8(+) ratio that decreased by more than 0.5 at 1 month after splenectomy was significantly lower than that in patients with a ratio that decreased by less than 0.5 (P < 0.05). CONCLUSION: Splenectomy may improve liver fibrosis and cause beneficial immunological changes in cirrhotic patients with hepatitis. Improvements in antitumor mechanisms can be also expected.

Gemcitabine with paclitaxel therapy against mesocolic leiomyosarcoma: a case report.

A 65-year-old man complained of lower right abdominal pain, and an intra-abdominal mass was identified. An intra-abdominal hemorrhage was discovered during a thorough examination and emergency surgery was performed. The tumor was ruptured and was fragile, making it difficult to perform extirpation; thus, an ileocecal resection was performed. The histopathological diagnosis of the tumor was leiomyosarcoma, and recurrence was observed during the early postoperative period. The patient underwent surgery twice; each time there was a recurrence, but complete resection could not be obtained, and paclitaxel and gemcitabine chemotherapy was performed. A temporary effect was observed, and control of disease progression lasted approximately five months. Standard chemotherapy for leiomyosarcoma has not been established, but this method could become a therapeutic strategy for leiomyosarcoma.

Epstein-Barr virus-associated primary central nervous system cytotoxic T-cell lymphoma.

Primary central nervous system lymphoma (PCNSL) expressing T-cell markers is rare, among which nasal-type extranodal NK/T-cell lymphoma is an extremely rare subtype associated with Epstein-Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV-associated PCNSL showing a cytotoxic T-cell phenotype. The patient, a 73-year-old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion recovery images, and slightly hyperintense on diffusion-weighted images. Biopsy specimens from the temporal region showed many medium-sized anaplastic lymphocytic cells with perivascular and angio-invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T-cell-restricted intracellular antigen-1 (TIA-1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV-encoded RNAs in the tumor cell nuclei. A rearrangement study showed T-cell receptor γ-chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T-cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV-associated T-cell lymphoma.

Epstein-Barr virus and methotrexate-related CNS lymphoma in a patient with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA), especially those treated with methotrexate (MTX), might have an increased risk of lymphoproliferative disorders that are associated with Epstein-Barr virus (EBV). We describe a case of EBV-associated central nervous system (CNS) lymphoma (diffuse large B-cell lymphoma) in a patient with RA on a short course of MTX treatment. The neoplastic cells express the B-cell surface markers (CD20, Pax-5 and CD30), and EBV-encoded RNA was demonstrated by in situ hybridization. The patient's lymphoma did not recur for the 8-year follow-up period after the tumor resection and cessation of MTX. MTX may promote EBV-positive CNS lymphoma in RA patient due to its immunosuppressive properties as well as reactivating latent EBV infection.