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We present a case of an angioimmunoblastic T-cell lymphoma (AITL) and tubulointerstitial nephritis with storiform fibrosis in a 76-year-old man. The patient exhibited lymphadenopathy, polyclonal hypergammaglobulinemia, and renal dysfunction and was diagnosed with AITL on the basis of lymph node biopsy findings. The serum IgG4 level was highly elevated. Renal biopsy revealed IgG4-positive plasma cells and storiform fibrosis without infiltration of AITL, and the findings indicated IgG4-related kidney disease (IgG4-RKD). Following THPCOP therapy for AITL, the renal function improved. While diagnosing IgG4-RKD in a patient with AITL poses challenges, follicular helper T cell involvement appeared crucial in AITL and renal tubulointerstitial lesions in this case., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Chronic lymphocytic leukemia (CLL) is rare in Japan. We conducted the nationwide, prospective observational study CLLRSG-01 to clarify the current state of CLL in Japan and to make accurate international comparisons by preparing naturally air-dried smears like those used in other countries. Of the 201 untreated patients enrolled and evaluated, 119 were diagnosed with CLL and 82 with non-CLL mature B-cell neoplasms, based on the WHO classification. Of the 119 CLL patients, 90 were classified as typical and 29 as atypical according to FAB classification morphology, with the proportion of atypical CLL consistent with reports from other countries. Immunophenotypic analyses by flow cytometry showed that 55% of Japanese CLL patients had a Matutes score of 4 or higher, which is lower than the rate of about 90% in Europeans. Mutated IGHV was identified in 80% of Japanese CLL patients, which is a higher rate than in Western patients. The most frequent IGHV gene was VH3-30 (15%), followed by VH3-23 (12%) and VH4-34 (10%). VH1-69, the most common gene in Western countries, was identified in only one patient. These results indicate that the pattern of immunophenotypes and IGHV gene usage in Japanese CLL patients differs from that in Western patients., (© 2024. Japanese Society of Hematology.)

Chronic active Epstein-Barr virus disease (CAEBV), formerly named chronic active Epstein-Barr virus infection, is characterized by systemic inflammation and clonal proliferation of Epstein-Barr virus (EBV)-infected T or NK cells. As CAEBV is a potentially life-threatening illness, appropriate diagnosis and therapeutic interventions are necessary for favorable clinical outcomes. Substantial evidence regarding the pathogenesis and treatment of CAEBV has been accumulated since previous guidelines for the diagnosis of CAEBV were proposed. To reflect this evidence, we updated the guidelines for the diagnosis and treatment of CAEBV to improve clinical management of the disease. The details of the updated guidelines are presented in this report. Diagnosis of CAEBV now requires confirmation of a high copy number of EBV genome and EBV-infected T or NK cells. An EBV DNA load ≥ 10,000 IU/mL in whole blood is proposed as the diagnostic cutoff value for CAEBV in this updated guideline. A standard treatment approach for CAEBV has not been established, and hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment. Chemotherapy can be administered to control disease activity before HSCT., (© 2023. The Author(s).)

Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the "iATL-PI," has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses., (© 2022. Japanese Society of Hematology.)

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG., (© 2021. Japanese Society of Hematology.)

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation. In addition to reactivation of Epstein-Barr virus in immunocompromised patients, impaired tumor immunity is suggested to be a risk factor for PTLD. However, it remains unclear whether immune suppressive tumor-infiltrating lymphocytes (TILs) correlate with the occurrence or prognosis of PTLD. We analyzed TILs in 26 patients with PTLD to elucidate the clinicopathological significance of the expression of PD-1 and FoxP3, which are associated with exhausted T-cells and regulatory T-cells (Tregs), respectively. Numbers of PD-1 + TILs in the PTLD specimens were significantly higher in patients who developed PTLD early after transplantation (P = 0.0040), while numbers of FoxP3 + TILs were not (P = 0.184). There was no difference in overall response rate regardless of the expression of PD-1 or FoxP3. FoxP3 high patients tended to have a shorter time to progression compared with FoxP3 low patients, especially in the case of FoxP3 high patients with diffuse large B-cell lymphoma-subtype PTLD (P = 0.011), while PD-1 high patients did not. These results suggest that T-cell exhaustion may be mainly associated with PTLD development, while immune suppression by Tregs may be dominant in enhanced progression of PTLD following disease occurrence.

Programmed death 1 ligand (PD-L1) is an immunomodulatory molecule expressed by cancer cells, and it has been widely demonstrated to inhibit host antitumor responses. The aim of the present study was to identify clinicopathological features associated with PD-L1 expression in the secondary solid cancers of patients after allogeneic hematopoietic stem cell transplantation. In this database of 530 patients who received allo-HSCT between 1990 and 2017, 15 developed solid cancers with a median interval of 3487 days after transplantation. Three patients had 2 different solid cancers. Eighteen solid cancer cases were identified. A multivariate analysis showed that chronic graft-versus-host disease (GVHD) was associated with an increased risk of solid cancer. The presence of chronic GVHD was observed in 8 out of 18 cases at the diagnosis of secondary malignancies. PD-L1 expression levels in cancers were significantly higher in patients with active chronic GVHD than in those without chronic GVHD (P = 0.020). Five cases of cancer that developed in the involved organs of chronic GVHD showed 30% or higher PD-L1 positivity. The present results revealed distinct PD-L1 expression in the secondary solid cancers of post-transplant patients with chronic GVHD.

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate-high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.

Allogeneic hematopoietic cell transplantation (allo-HSCT) is considered the curative treatment option in patients with aggressive adult T cell leukemia/lymphoma (ATLL), but the treatment of relapse after allo-HSCT remains a major challenge. We report a case of ATLL that was treated with sequential mogamulizumab (MOG) and lenalidomide (LEN) for early relapse after allo-HSCT. A 73-year-old Japanese male with acute-type ATLL underwent haploidentical-HSCT with post-transplant cyclophosphamide. He attained a complete response. However, ATLL relapse was diagnosed by biopsy of skin lesions that appeared on day 67. Discontinuation of immunosuppressant therapy alone did not result in improvement of ATLL, however, the skin lesions disappeared after an immune response was induced by sequential MOG and LEN. Following MOG and LEN, very serious toxic epidermal necrolysis (TEN) developed requiring high-dose intravenous immunoglobulin and methylprednisolone pulse therapy. Although graft-versus-host disease exacerbated and progressed to TEN, a complete response was achieved after successful treatment of TEN. These agents may thus enhance anti-ATLL activity by immune modulation. Further investigation is necessary to determine the optimal use of MOG and LEN in relapsed ATLL after allo-HSCT.

The frequency of multiple primary malignant neoplasms (MPMN) is increasing due to population aging. Since consensus guidelines for the treatment of MPMN are lacking, treatment strategies are determined by disease status on a per-patient basis. In this report, we describe a case of MPMN with follicular lymphoma (FL) grade 1 that transformed to double-hit lymphoma during adjuvant chemotherapy for concurrent ovarian carcinoma. A 64-year-old woman was diagnosed with MPMN of FL and endometrioid carcinoma by staging laparotomy and lymph node biopsy. She received four cycles of adjuvant chemotherapy (carboplatin and paclitaxel) for endometrioid carcinoma, but during chemotherapy, the FL grade 1 transformed to double-hit lymphoma. We speculate that adjuvant chemotherapy for endometrioid carcinoma may have triggered the transformation of FL in the present case.

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.

Composite lymphoma (CL) is a rare disorder defined as the coexistence of two or more distinct lymphoma subtypes at a single anatomic site. Discordant lymphoma (DL), which is the simultaneous occurrence of two or more distinct lymphoma subtypes at different sites, is also rare. CL complicated with DL involving three distinct subtypes of lymphoma in the same patient is an extremely rare disease. Clonal relationships in CL and DL are commonly investigated by molecular analysis using mutational status with t(14;18)BCL2/IgH translocation and immunoglobulin heavy chain variable-region (IgV H ) gene rearrangement. A 73-year-old woman was admitted to our hospital with systemic lymphadenopathy and was initially diagnosed with diffuse large B-cell lymphoma based on pathological features of the biopsied esophageal tumor. However, the results of inguinal lymph node biopsy led to a revised pathological diagnosis CL consisting of Hodgkin lymphoma and follicular lymphoma. Three distinct coexisting lymphomas were identified in this individual patient. Molecular analysis revealed CL derived from common germinal center B-cell precursors, while clonal relationship between CL and DL was not clarified. This case suggests a mechanism underlying B-cell lymphoma pathogenesis involving two pivotal somatic mutations, t(14;18)BCL2/IgH translocation and IgV H rearrangement.

The morbidity and mortality of disease vary according to the region and may also change over time. The morbidity and mortality of malignant lymphoma are also affected by differences in ethnicity, lifestyle habits, geographical area, and time period. Increasing research on malignant lymphoma has focused on its pathophysiology, diagnosis, and therapeutic treatment. Recent improvements in the accuracy of clinical study, technologies such as next-generation sequencing, and the development of targeted molecular agents have also resulted in a number of excellent studies. This review summarizes the epidemiology of malignant lymphoma and highlights novel studies on adult T-cell leukemia/lymphoma recently published in Japan.

TAFRO syndrome is a rare variant type of multicentric Castleman disease, which is characterized by thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly. Here, we report a case of TAFRO syndrome that was successfully treated with tocilizumab. A 50-year-old man, who presented with fever, epigastric pain, abdominal fullness, and massive edema of the extremities, was admitted to our hospital. Computed tomography revealed bilateral pleural effusions, ascites, and lymphadenopathy. Laboratory data showed renal dysfunction, anemia, and thrombocytopenia. Examination of bone marrow and cervical lymph nodes led to a diagnosis of hyaline vascular-type Castleman disease. The level of serum interleukin (IL)-6 was extremely high. TAFRO syndrome was finally diagnosed. The patient was treated weekly with tocilizumab, an anti-IL-6 receptor antibody and steroids. In 4 weeks, all symptoms disappeared and serum IL-6 level returned to normal. Activity of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which was significantly decreased (9.9 %) prior to treatment, increased after treatment with tocilizumab. The present case suggests that tocilizumab is an effective therapeutic agent for TAFRO syndrome. We suggest that hypercytokinemia in TAFRO syndrome inhibits ADAMTS13 activity, thereby inducing thrombotic microangiopathy.

There have been rare reported cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) that co-expressed CD20. A 44-year-old Japanese male was initially misdiagnosed as CD20-positive diffuse large B-cell lymphoma with a background of reactive CD3-positive T-cells in the stomach. After four cycles of R-CHOP [rituximab plus cyclophosphamide (CY), doxorubicin, vincristine, and prednisolone (PSL)], total gastrectomy with regional lymph node dissection was performed due to the poor response to R-CHOP. A final diagnosis of CD20-positive primary gastric PTCL-NOS was made based on the immunohistochemical, flow cytometric, and molecular genetic findings. In the present case, CD20 immunostaining for T-cell lymphoma cells in tumor tissue varied; in a large part, these were strong to weak-positive, and in some parts, absent. We additionally reviewed the literature focusing on CD20-positive PTCL-NOS treated with rituximab. The administration of rituximab has been performed as an initial treatment in 11 cases, including the case reported here. The response was good in cases with high expression of CD20, while it was poor in cases with variable intensity in CD20 staining, which is consistent with our experience in the present case. The efficacy of rituximab may be associated with intensity of CD20 expression in T cells and its homogeneity in the tumor tissue.

Secondary non-Hodgkin lymphoma following acute myeloid leukemia (AML) is extremely rare. We here describe a unique case involving a patient who developed Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) during complete remission (CR) of AML. A 75-year-old Japanese man was initially diagnosed with AML with maturation (FAB M2), bearing chromosomal translocation t(3,4)(p25;q21). After intensive chemotherapy, bone marrow aspiration revealed normal karyotype, and he achieved CR. Six years and 4 months later, he was still in CR from AML, but developed DLBCL presenting in the terminal ileum. Cytogenetic analysis of the DLBCL cells showed the same translocation as the previous AML. The rearrangements of the immunoglobulin heavy chain genes of the two malignancies were examined using polymerase chain reaction amplification, and the rearrangement patterns were found to differ from each other. Our data thus suggest that, in the present case, the AML and DLBCL arose from a common progenitor cell, as indicated by the clonal abnormality t(3,4)(p25;q21), and that different immunoglobulin heavy chain gene rearrangements occurred during each course of clonal evolution.

Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with the retrovirus, human T-cell leukemia virus type I (HTLV-I). In a previous series of studies, our group and others characterized the histopathological changes in HTLV-I-associated lymph node lesions. In addition to the pleomorphic and anaplastic large cell types of typical ATL lymphoma, we identified lymph nodes with an unusual Hodgkin's disease-like histology (Hodgkin-like ATLL) in HTLV-I-positive patients, with Hodgkin-like ATLL showing prodromal clinical features. We also reported HTLV-I-associated lymphadenitis, characterized by non-neoplastic HTLV-I-associated lymph node lesions. It has become clear that the biological and clinical behavior of malignant lymphoma is not only determined by the properties of the lymphoma cells themselves, but also largely by the interaction of these cells with their nonmalignant microenvironment. In this review, we discuss the pathological variations of microenvironments, which are important for clarification of the histological features associated with HTLV-I.

We report a case of a 40-year-old female who developed progressive multifocal leukoencephalopathy (PML), which is associated with JC virus reactivation, after allogeneic hematopoietic cell transplantation. As she had been suffering from graft-versus-host disease and lung damage after pneumocystis pneumonia, the administration of calcineurin inhibitor and steroid could not be discontinued. However, she showed a favorable improvement in clinical symptoms and imaging findings after treatment with the anti-malarial drug, mefloquine and a serotonin receptor blocker, mirtazapine. Continuation of the treatment for eight months finally led to the clearance of the JC virus from her cerebrospinal fluid. She currently shows no neurological disturbance and has resumed her daily activities. PML due to the severe immunosuppressive condition has been reported as a fatal complication after allo-SCT. Our case suggests that combination treatment with mefloquine and mirtazapine may be of great value for the treatment for PML patients in the post allo-SCT setting, although it is difficult to say whether the combination treatment alone led to improvement. Further clinical study is needed to clarify the efficacy of these drugs for the treatment of PML.

Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source; however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation.

The small cell variant of anaplastic large cell lymphoma (ALCL) presents in a nearly identical manner to the more common ALK(+) primary ALCL, with the exception that it is more frequently associated with leukemic involvement, and the prognosis has been reported to be poor. We report a 40-year-old Japanese male who was diagnosed with small cell variant ALCL with peripheral blood involvement stage IVB, age-adjusted international prognostic index 3. Conventional cytogenetics of the bone marrow aspirate specimen showed abnormal metaphases with the following karyotype: 47, XY, +X, t(2;5)(p23;q35). The patient was treated with acute lymphoblastic leukemia-oriented intensive chemotherapy. He underwent allogeneic peripheral blood stem cell transplantation from his HLA-DR1 locus mismatch sister. Prior to transplant, the patient had residual lymphadenopathy considered to be in partial remission. As of August 2012, the patient has achieved 18 months of continuous complete remission (CCR), with a Karnofsky score of 100 %. We have identified a total of seven cases of small cell variant ALCL treated with allogeneic hematopoietic stem cell transplantation (HSCT) in the literature. Of these, no relapse was reported, and four patients were CCR more than 1 year. Allogeneic HSCT appears to represent a promising treatment option for small cell variant ALCL.

Positron emission tomography (PET) is used for staging and response evaluation in primary gastric lymphoma (PGL). However, the implications of [(18)F]-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in PGL at first diagnosis have not been reported. The relationship between (18)F-FDG uptake and the expression of facilitative glucose transporters (GLUTs), hexokinase II (HK II), and Ki67, as well as malignant potential in PGL, was assessed in this study. We analyzed 23 patients with PGL [nine with diffuse large B-cell lymphoma (DLBCL); seven with high-grade mucosa-associated lymphoid tissue (MALT) lymphoma; and seven with low-grade MALT lymphoma]. The expression levels of GLUT1, GLUT3, HK II, and Ki67 were evaluated according to the percentage of positive area determined by immunohistochemistry. Standardized uptake values correlated significantly with pathological malignant potentials (low-grade/high-grade MALT lymphoma and DLBCL: p = 0.001-0.002), Ki67 (p < 0.001), and GLUT1 expression (p = 0.02). We determined that (18)F-FDG uptake is related to GLUT1 expression and tumor histological grade as well as Ki67 in PGL.

We report the results of unrelated cord blood transplantation (UCBT) for patients with adult T-cell leukemia/lymphoma (ATLL) conducted in our single institute. Ten patients with ATLL (nine acute and one lymphoma-type) received UCBT during the period from August 2003 to July 2011. The median age at the time of diagnosis of ATLL was 51 years (range 37-64). The median period from diagnosis of ATLL to UCBT was 130 days (range 94-344). Conditioning regimens were myeloablative for six and reduced intensity for four. The median number of infused nucleated cells and CD34 positive cells were 2.52 × 10(7)/kg and 1.04 × 10(5)/kg, respectively. There was no engraftment failure. Three patients developed grade II acute graft versus host disease, and four developed grade III. The estimated 2-year overall survival was 40 % (95 % CI 12-67 %). Four of six chemosensitive patients prior to UCBT survived for 1035, 793, 712, and 531 days post-UCBT, respectively. There were no survivors among the four chemorefractory patients prior to UCBT. Our data indicates that UCBT is feasible and provides long-term survival in patients with chemosensitive ATLL.

Angioimmunoblastic lymphoma (AITL) is a nodal peripheral T-cell lymphoma characterized by a proliferation of arborizing vessels and hyperplastic follicular dendritic cells as well as a polymorphous lymphoid infiltrate including neoplastic cells with clear cytoplasm. Adult T-cell leukemia/lymphoma (ATLL) is caused by the retrovirus human T-cell leukemia virus type I (HTLV-I), and the neoplastic cells are usually large and pleomorphic. Recently, a rare morphologic variant of ATLL with AITL-like features has been reported. Here, we presented a case of peripheral T-cell lymphoma with morphological features of AITL in Taiwan, a country non-endemic for HTLV, and the patient was seropositive for anti-HTLV antibody, which raised the possibility of ATLL with AITL-like features. Immunohistochemically, there were hyperplastic follicular dendritic meshworks by CD21 immunostaining, and the neoplastic cells expressed CD10, programmed death-1, and CXCL13. Furthermore, Southern blot analysis using DNA extracted from the nodal tissue was negative for HTLV-I proviral integration. Our investigations indicated that in an HTLV-I non-endemic area, a peripheral T-cell lymphoma with typical morphologic and immunophenotypic features of AITL could be confidently diagnosed as AITL even if the patient was seropositive for anti-HTLV antibody.

Peripheral T cell lymphoma not otherwise specified (PTCL-N) and ALK-negative anaplastic large cell lymphoma (ALCL) are heterogeneous categories with poor diagnostic reproducibility. To clarify the biologic features of these categories, we investigated the expression of two chemokine receptors, type 1 (Th1/Tc1)-associated CXCR3 and type 2 (Th2/Tc2)-associated CCR4 in 110 PTCL-N and 35 ALK-negative ALCL cases, as well as the expression of cytotoxic molecules (CM). CXCR3 and CCR4 were expressed in 69 (63%) and 37 (34%) of PTCL-N, and in 12 (34%) and 6 (17%) of ALK-negative ALCL, respectively. In PTCL-N, type 1 pattern (CXCR3(+)CCR4(-)) was dominant (52%), whereas in ALK-negative ALCL, 54% were negative for both (P < 0.0001). CM was expressed in 38% of PTCL-N and 51% of ALK-negative ALCL. CM-positive PTCL-N consisted mostly of type 1 disease, which shows type 1 phenotype. In contrast, type 2 pattern (CXCR3(-)CCR4(+)) was recognized in the CM-negative group only. Among type 1 disease, CM-positive cases had a higher female ratio and more aggressive clinical features than CM-negative cases and a poorer prognosis (P = 0.006). Multivariate analysis confirmed that the type 1 phenotype with CM expression was an independent prognostic factor. In both PTCL-N and ALK-negative ALCL, CM-positive type 1 disease had an extremely poor prognosis.

We performed a retrospective analysis of patients with diffuse large B cell lymphoma treated with rituximab plus CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) as a first-line therapy at 22 hospitals of the Kyushu Lymphoma Study Group. During the period 1996-2005, 1,057 patients (aged 22-90 years) were analyzed. Of these, 678 were treated with CHOP, and 379 were treated with rituximab plus CHOP (R-CHOP). The complete response rate was 59.9% in the CHOP group and 67.0% in the R-CHOP group (P < 0.001). Three-year progression-free survival (PFS) and overall survival (OS) rates were significantly higher in the R-CHOP group than in the CHOP group (61.3 vs. 45.6% for PFS, P < 0.001; 68.3 vs. 54.5% for OS, P < 0.001). The International Prognostic Index was a good prognostic marker for both groups; a survival benefit of rituximab addition was found for each risk subgroup and also for both age groups (60 years). Among 345 patients who received localized radiation therapy, the adding rituximab to CHOP attenuated the survival difference between CHOP and R-CHOP groups (P = 0.104), compared with no radiation group (P < 0.001). Results of this large-scale, multicenter study confirm that rituximab plus CHOP provided a greater survival benefit than CHOP alone.

We previously reported that the prognosis of CD21-positive diffuse large B-cell lymphoma (DLBCL) is significantly favorable to that of CD21-negative DLBCL (Otsuka et al. in Br J Haematol 127:416-424, 2004). In this study, we attempted to clarify the biological significance of CD21 expression in B-cell lymphoma (BCL) by performing in vitro experiments using CD21 transfection into a CD21-negative lymphoma cell line and analyzing clinical data from lymphoma samples. Established clones of CD21 transfectants showed homotypic aggregation in suspension culture. Analysis of integrin expression revealed that LFA-1 appeared to be expressed on CD21 transfectants, and the cell aggregation was abrogated by anti-LFA-1 antibody. The CD21 transfectants could adhere to plastic plates coated with ICAM-1. Moreover, flow cytometry and/or immunohistochemical analyses of clinical BCL samples (n = 29) revealed positive for CD21 in all cases; LFA-1 was also expressed without exception. All BCL cells isolated from cavity fluids (n = 10) failed to express both CD21 and LFA-1. These data suggest that CD21 is tightly related to LFA-1 expression in BCL and the absence of CD21/LFA-1 expression is associated with pleural/peritoneal fluid involvement by BCL, a potential indicator of disease progression of BCL.

A 26-year-old female diagnosed as mycosis fungoides (MF, clinical stage IV) was treated with single-agent chemotherapy, multi-drug chemotherapy and unrelated bone marrow transplantation with reduced-intensity conditioning (engraftment failure), resulting in failure. Unrelated cord blood transplantation (CBT) as second transplantation following myeloablative conditioning brought complete remission (CR), but relapse of MF occurred 3 months after transplantation. However, discontinuation of immune suppressant led to the regression of MF regions and to second CR that continued for more than 23 months. This is the first report of successful CBT for MF, suggesting the graft-versus-MF effect in a setting of CBT.

The case concerns a 55-year-old Japanese man with multiple pancreatic tumors that were incidentally detected by ultrasonography (US) in a routine medical examination. He consulted a doctor since either neuroendocrine tumors or metastases of small-cell lung carcinoma were suspected, because he had an abnormal shadow in the lung. Then he was transferred to our hospital. Imaging studies showed multiple pancreatic tumors of 3.0-cm diameter in the head, 1.0 cm in the body and 1.5 cm in the tail, respectively. Specimen by endoscopic ultrasonography fine-needle aspiration cytology (EUS-FNAC) revealed numerous B-cell lymphocytes, but a definite diagnosis of malignant lymphoma could not be obtained. Therefore, a segmental pancreatic body resection was performed to clarify the features of the tumor for appropriate therapy. Consequently, the final diagnosis was obtained as a low-grade B-cell lymphoma having a lymphoepithelial lesion, which indicated mucosa-associated lymphoid tissue (MALT) lymphoma. Radiation therapy with 31 Gy successfully resulted in complete remission. We report here for the first time on primary pancreatic low-grade MALT lymphoma presenting with multiple pancreatic masses.

Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.

Epstein-Barr virus (EBV) is closely associated with several lymphomas, such as Burkitt lymphoma, natural killer/T-cell lymphoma, peripheral T-cell lymphoma, and Hodgkin's lymphoma; however, whether EBV is implicated in mantle cell lymphoma (MCL) has not been established. We report the case of an adult with recurrent infectious mononucleosis (IM)-like symptoms who developed an EBV-positive blastoid variant of MCL. A 54-year-old Japanese man presented with fever, swelling of the oral mucosa and tongue, dispersed pulmonary infiltrations, systemic lymphadenopathy, and splenomegaly. He had a history of recurrent IM-like symptoms (prolonged fever and cervical lymphadenopathy) for at least 1 year. MCL was diagnosed by biopsy of the cervical lymph node. The anti-EBV antibody titer indicated a reactivation of chronic infection with this virus. EBV was detected in most of the lymphoma cells and in the peripheral blood. EBV might have played some role in the tumorigenesis of blastoid MCL.

Approximately 20% of mantle cell lymphomas (MCL) present with the blastoid variant associated with poor prognosis. Lactic acidosis complicated with hematologic malignancies is seen infrequently and is associated with a poor outcome. Here we report the case of a patient with the blastoid variant of MCL complicated by lactic acidosis and who achieved complete remission through chemotherapy combined with rituximab therapy. A 77-year-old man presented with peripheral blood lymphoma cells, huge splenomegaly, abdominal and mediastinal lymphadenopathy, and pleural effusion. A bone marrow smear showed an increase in large, abnormal lymphoid cells with oval or round nuclei, distinct nucleoli, and abundant basophilic cytoplasm with vacuolization. Splenic sections also showed massive and diffuse infiltration by these cells. Flow cytometry analysis showed these cells to be positive for CD5, CD19, CD20, and kappa chain and negative for CD10 and CD23. A blastoid variant of MCL was diagnosed from the results of histologic, immunohistochemical (cyclin D1), and cytogenetic (chimeric bcl-1/IgH fusion gene) analyses. The patient recovered from the 2 episodes of severe lactic acidosis for which he had been given chemotherapy, and he achieved complete remission after subsequent chemotherapy combined with rituximab treatment.

In human cancer, RCAS1 (the receptor-binding cancer antigen expressed on SiSo cells) on the surface of various kinds of tumor cells reportedly induces the apoptosis of T-cells and natural killer cells, resulting in evasion of the immune system. In the present study, an immunohistochemical analysis of RCAS1 expression was performed with lymph node specimens obtained from patients with adult T-cell leukemia/lymphoma (ATLL). Positive staining was seen in 15 (75%) of 20 cases and in all cases of patients with short survival times. In the cases of B-cell lymphomas, positive staining was seen in only 1 (13%) of 8 cases. These findings indicate that expression of RCAS1 may be associated with the evasion from immune surveillance of cells infected with human T-lymphotropic virus type I, resulting in the development of overt leukemia/lymphoma. Determination of RCAS1 expression may be useful for predicting the prognosis of patients with ATLL.

Enteropathy-type T-cell lymphoma (ETCL) is a rare extranodal lymphoma that tends to disseminate into the intestines and other extranodal organs. We present a case of ETCL with involvement of the lungs and kidneys and report CC chemokine receptor 7 (CCR7) expression of lymphoma cells. A 73-year-old man was admitted to the hospital with a complaint of abdominal pain. Multiple ulcers and perforations were observed in the small intestine, and partial resection of the ileum was performed. Histological examination of the resected specimen revealed diffuse proliferation of atypical large lymphoid cells. The diagnosis was ETCL with dissemination into the lungs and kidney. Lymphoma cells of the small intestine and in pleural effusion were CD3+, CD4+, CD7+, CD8-, CD25-, CD56-, CD103 +/-, and TIA-1+. Rearrangement of the T-cell receptor beta gene was detected, and human T-lymphotropic virus was not integrated. Combination chemotherapy did not result in a sustained response. The results for CCR7 expression of lymphoma cells in the lung and pleural effusion were negative. Therefore we concluded that lymphoma cells did not migrate into the lymph nodes but instead spread into the extranodal organs.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1), which is recognized by the 22-1-1 monoclonal antibody (MoAb) against human uterine adenocarcinoma cell line SiSo, has been identified on various kinds of cancer cells. RCAS1 appears to be an apoptosis-associated protein that induces apoptosis in activated T-cells and erythroid progenitor cells. We previously demonstrated that monocytes/macrophages express RCAS1. In the present study, we investigated RCAS1 expression by 22-1-1 MoAb in histiocytic necrotizing lymphadenitis (HNL), which is characterized by necrotic lesions consisting of T-cells undergoing apoptosis and macrophages in proliferation. Expression of RCAS1 was analyzed by immunohistochemical staining in 9 cases of HNL and in 9 cases of reactive lymphadenitis used as a control. The ratio of RCAS1+ cells to CD68+ cells (monocytes/macrophages) was significantly higher in the patients with HNL than in the patients with reactive lymphadenitis (P = .0002; paired t test). Our findings suggest that RCAS1 expressed on macrophages may play an important role in the induction of activated T-cell apoptosis in cases of HNL.

Formalin-fixed paraffin-embedded lymph node samples were collected from 100 cases of malignant nodal lymphoma documented in Okinawa in the period from 1973 through 1998. According to the new World Health Organization classification, 12 cases were Hodgkin's lymphoma (HL). Eighty-eight cases of non-Hodgkin's lymphoma (NHL) included 54 cases of T-cell type and 34 cases of B-cell type. Using polymerase chain reaction (PCR), Epstein-Barr virus (EBV) was detected in 11 cases (91.7%) of HL and in 57 cases (64.8%) of NHL, and human T-cell lymphotropic virus type 1 (HTLV-1) was detected in 23 cases (26.1%) of NHL. Clonal integration of HTLV-1 was detected in 10 (43.5%) of 23 HTLV-1 PCR-positive cases by the inverse PCR technique. The EBV-infected cells were detected by EBER-1 in situ hybridization in 11 (91.7%) of 12 HL cases and in 64 (72.7%) of 88 NHL cases. Irrespective of phenotype and tissue type of the malignant lymphoma, the rate of EBV-positive infection in Okinawa was higher than that in any other districts reported in Japan. This characteristic high rate of EBV-positive infection in Okinawa can be ascribed to various factors, such as racial and geographical differences.

A 60-year-old Japanese woman who presented with right nasal congestion and high fever was admitted to our hospital in March 1999. She was diagnosed with nasal NK/T-cell lymphoma clinical stage IVB. Because her NK/T-cell lymphoma was highly aggressive and chemo-resistant, she underwent autologous peripheral blood stem cell transplantation (PBSCT). The patient received a pretransplantation conditioning regimen of ranimustine, etoposide, carboplatin, and cyclophosphamide. On July 29, 1999, 1.0 x 10(6)/kg CD34+ cells were infused. The patient achieved first complete remission. In January 2000, NK/T-cell lymphoma relapsed in the skin and fever developed. CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisolone) was administered, resulting in partial regression of the skin lesions, but fever persisted. L-asparaginase (L-Asp) at a dose of 6,000 U/m2 per day was administered for 7 days, resulting in the complete disappearance of the skin lesions and resolution of the fever. The patient has been in second complete remission for more than 18 months since the completion of L-Asp treatment (as of July 2001). The effect of L-Asp in this patient was dramatic. Several cases have been reported describing the effectiveness of L-Asp in patients with nasal lymphoma and cutaneous T-cell lymphoma. A front-line chemotherapy regimen containing L-Asp for NK/T-cell lymphoma may warrant further evaluation.

Recent studies have indicated that Fas and perforin-based mechanisms seem to induce apoptosis in histiocytic necrotizing lymphadenitis (HNL). In this study, we evaluated the serum levels of soluble Fas ligand (sFasL) in 30 HNL patients using paired sera. Elevations in sFasL levels were detected in 9 patients in the active stage. In the convalescent stage, the levels of sFasL decreased to an undetectable degree after 2 weeks. These findings indicate the possibility that sFasL plays an important role in the constitutional symptoms and pathogenesis of HNL and, furthermore, that it can act as a surrogate marker of the disease activity.

Recently, we showed that 5 cases of hypersensitivity to mosquito bites (HMB) concealed the clonal lymphoproliferation of Epstein-Barr viral (EBV) DNA-positive natural killer (NK) cells. Although the symptoms of HMB have been supposed to derive from Arthus phenomenon, it has become apparent that this unique disorder has the potential to develop into so-called malignant histiocytosis (MH) or related disorders. Accordingly, the criteria for MH have been changed, and a newer diagnostic name, hemophagocytic syndrome, has been described as being associated with viral infection or leukemia/lymphoma. We previously reported that biopsy specimens taken from skin lesions demonstrated infiltration of lymphocytes bearing the phenotype of NK cells. In this study, we found that skin lesions exhibited infiltration of atypical lymphocytes around the small vessels, resembling angiocentric lymphoma, and that these infiltrating cells were positive for EBER-1 by in situ hybridization. These findings support the concept that HMB is the most important manifestation of a certain type of lymphoproliferative disease that presents with an intense local skin reaction and high fever following mosquito bites, and whose essence is the lymphoproliferation of EBV DNA-positive NK cells.

To determine the pathogenesis of hemophagocytic lymphohistiocytosis (HLH), serum levels of neuron-specific enolase (NSE) and cytokine profiles were investigated. Serum concentrations of NSE and several cytokines were measured by immunoassays, and the association was evaluated in 18 HLH patients. Serum NSE levels increased (> 10 ng/mL) in 27/29 samples (93%) during the active febrile phase, the mean level of which (35.9 ng/mL) was much higher than that during the remission phase (11.2 ng/mL) (P = .001). The peak levels of NSE in 11 patients who required cytotoxic agents were higher than those in 7 patients without chemotherapy, 64.6 +/- 49.4 and 17.9 +/- 12.9, respectively (P = .265). The NSE levels correlated positively with the levels of interferon (IFN)-gamma (Pearson's correlation coefficient [r] = 0.408, P = .044), soluble interleukin-2 receptor (sIL-2R) (r = 0.464, P = .048), lactate dehydrogenase (r = 0.830, P < .00001), aspartate aminotransferase (r = 0.531, P = .003), and ferritin (r = 0.715, P < .00001), and correlated negatively with platelet count (r = -0.422, P = .021), but not with other parameters, including tumor necrosis factor-alpha, IL-1 beta, IL-18, soluble Fas ligand and C-reactive protein. Multiple regression analysis indicated that the correlation of NSE with platelet count was independent of other correlations. Sequential NSE changes well reflected the clinical course of patients. Immunohistochemical staining revealed an appreciable number of NSE-positive histiocytes in bone marrow specimens with florid hemophagocytosis. These results suggest that the circulating NSE originated from macrophages stimulated with IFN-gamma/sIL-2R, and partly from the destruction of platelets. Serum NSE level may be a useful marker for predicting the disease progression of HLH.

We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver. Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells. Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.

A 75-year-old female was admitted to our hospital because of shortness of breath and palpitations. Chest roentgenogram together with a CT scan showed multiple nodular shadows in both lung fields, with hilar lymphadenopathy. The cervical lymph nodes were enlarged, and were biopsied to reveal diffuse large T-cell non-Hodgkin's lymphoma. Extensive pulmonary involvement was suspected and treatment with a modified CHOP regimen was begun. Following therapy, pulmonary symptoms were remarkably improved, and chest roentgenogram revealed virtually complete clearance of lung lesions. No severe side effects were observed as a result of the therapy.

Hepatobiliary scintigraphy was performed in 23 normal subjects and 47 patients with chronic liver disease (chronic hepatitis; n = 27, liver cirrhosis; n = 20) to evaluate its availability as a test of liver function. After intravenous administration of Tc-99m N-pyridoxyl-5-methyl-tryptophan, the data were acquired for 60 min and the time-activity curves of ROIs (the heart and liver) were generated. In two compartment model simulation, the early blood clearance rate (kl), late blood clearance rate (km), hepatic uptake rate (ku) hepatic excretion rate (ke), and hepatic excretion T 1/2 were calculated. There was no significant difference in those four k values in normal and chronic hepatitis. However, in liver cirrhosis each of them, except km, was lower than in normal subjects. The kl value correlated closely with the indocyanine green plasma clearance test, whereas the ke and T 1/2 values were closely correlated with the level of serum bilirubins. Only hepatobiliary scintigraphy showed the excretory function of the liver quantitatively and the ke value was helpful in detecting hepatic excretory dysfunction early in chronic liver disease before serum bilirubins increased.