A Case of Composite Lymphoma with Extranodal NK/T-cell Lymphoma, Nasal-type and Diffuse Large B-cell Lymphoma.

Composite lymphoma (CL) is defined as the occurrence of two distinct types of lymphoma within the same patient. Most cases of CL involve Hodgkin and non-Hodgkin lymphomas or two distinct types of B-cell lymphomas; true CL is a composite B-cell and T-cell lymphoma, and is rare. We herein report a case involving concurrent extranodal NK/T-cell lymphoma, nasal-type and diffuse large B-cell lymphoma, which has not been previously reported. As the mechanisms and treatments of composite B-cell and T-cell lymphomas are unclear, further studies are required to improve the prognosis.

Three cases of spontaneous splenic rupture in malignant lymphoma.

Spontaneous splenic rupture is a rare but often life-threatening condition. However, there is no consensus on appropriate management for this condition, due to its rarity. Here, we report three cases of malignant lymphoma with spontaneous splenic rupture. In each case, progression of splenic bleeding was rapid and complicated by malignant lymphoma. Spontaneous splenic rupture complicated by malignant lymphoma may cause exacerbation of anemia and hypovolemic shock. When splenic rupture is indicated by abdominal pain, tachycardia, or hypotension in a patient with splenomegaly, abdominal examination should be performed immediately, and emergency transcatheter arterial embolization and/or splenectomy should be considered.

Clinicopathological and genomic analysis of double-hit follicular lymphoma: comparison with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.

Clinicopathological Analysis of 320 Cases of Diffuse Large B-cell Lymphoma Using the Hans Classifier.

The estimation of clinical prognosis for diffuse large B-cell lymphoma (DLBCL) with a quick, cost-efficient method is necessary because of the clinical heterogeneity of this disease, which leads to death, relapsed or refractory disease in approximately 40% of patients. We analyzed 320 cases diagnosed from 2007 to 2013 treated with R-CHOP therapy at Tokai University Hospital and associated institutions. DLBCL was classified according to the cell-of-origin using the Hans algorithm [germinal center B-cell-like (GCB) vs non-GCB subtypes], and into 6 subgroups derived from combinations of CD10, BCL6 and MUM1 markers. The percentage of GCB and non-GCB (NGCB) subtypes was 35% and 65%, respectively. GCB-DLBCL was characterized by lower BCL2 immunohistochemical expression, extranodal sites ＜1, better therapeutic response, and favorable overall survival (OS) and progression free survival (PFS) (P＜0.01). The most frequent subgroup was NGCB-1 (CD10-BCL6+MUM1+, 51%) followed by GCB-1 (CD10+BCL6+or-MUM1+, 21%), NGCB-2 (CD10-BCL6-MUM1+, 13%), GCB-2 (CD10+BCL6+or-MUM1-, 10%), GCB-3 (CD10-BCL6+MUM1-, 4%) and NGCB-3 (CD10-BCL6-MUM1-, 2%). In comparison with GCB-2 and GCB-3 (both MUM1-), the GCB-1 (MUM1+) was characterized by favorable PFS (5-year PFS 84% vs 65%, OR 0.368, P＜0.05), independent of high LDH (associated with unfavorable PFS, OR 7.04, P＜0.01) in the multivariate analysis. This predictive value of MUM1 was independent of CD10. Interestingly, triple-negative NGCB-3 tended to have a more favorable prognosis than the other NGCB subgroups. In conclusion, the Hans classifier is a valid method to evaluate the prognosis of DLBCL NOS. In the GCB subtypes, GCB subtypes, MUM1-positivity is associated with a more favorable outcome (PFS).

Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation.

Previous studies have reported that an antibody that blocks programmed cell death 1 (PD-1) has therapeutic activity in patients with refractory/relapsed Hodgkin lymphoma (HL). However, the safety and efficacy of these agents in the post-allogeneic stem cell transplantation (allo-SCT) setting are not well known. Here, we describe a patient who was diagnosed as classical HL and treated with five regimens of chemotherapies with autologous SCT. Complete remission (CR) was not achieved following this initial treatment, so we performed allo-SCT from an HLA-matched sibling donor. Since his disease progressed at day 403 after allo-SCT, we decided to use nivolumab in the treatment of his refractory disease. To prevent the worsening of his chronic graft-versus-host disease (GVHD), we reduced the initial dose and frequency of nivolumab compared with the previous report. After four courses of 0.5 mg/kg of nivolumab every three weeks, FDG-PET imaging showed partial response (PR) to the treatment, a remarkable result. However, since the escalated dose of 2 mg/kg resulted in worsening of dyspnea and skin sclerosis, we initiated systemic administration of prednisolone and reduced nivolumab to 1 mg/kg. At the time of this report, his HL is in stable PR with three weekly administration of nivolumab and steroid controlled mild chronic GVHD.

Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBCL not otherwise specified (NOS).

AIMS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLsn ) in a series of 240 cases of DLBCL not otherwise specified [DLBCLall (NOS) ], including DLBCLsn training set (n = 11) and validation set (n = 18), and DLBCLnon-sn (n = 211). METHODS AND RESULTS: In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)+ . The genomic profile showed gains(+) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-) of 6q26q27 (55%) and 9p21.3 (64%); and copy number neutral loss of heterozygosity (LOH) (acquired uniparental disomy, UPD) at 6p25.3p21.31 (36%). This profile is comparable to DLBCLNOS (GSE11318, n = 203.) and closer to non-GCB/activated B-cell-like subtype (ABC). Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCLsn (P < 0.001). Array results were verified successfully by fluorescence in situ hybridization (FISH) on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), -9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82-91% agreement. Minimal common regions included biologically relevant genes of MNDA (+1q23.1), RGS1 and RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 (BLIMP1) and PARK2 (-6q21q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1) and BCL2 (+18q21.33). Correlation between DNA copy number and protein immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-like tumour associated macrophages (TAMs) and CD8+ T lymphocytes that associated with higher genomic instability. The DLBCLsn validation set confirmed the clinicopathological characteristics, all FISH loci and immunohistochemistry (IHC) for RGS1. RGS1, one of the most frequently altered genes, was analysed by IHC in DLBCLall and high RGS1 expression associated with non-GCB, EBER+ and unfavourable overall survival (hazard ratio = 1.794; P = 0.016). CONCLUSIONS: DLBCLsn has a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCLall (NOS) .

IgG4-related Disease with Bone Marrow Involvement.

A 61-year-old Japanese woman with anemia, submandibular gland swelling, and enlarged lymph nodes was diagnosed with IgG4-related disease (IgG4-RD) by lymph node biopsy. Bone marrow involvement of IgG4-RD was detected by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and immunohistochemically proven by bone marrow biopsy in this patient. Anemia progressed gradually, and prednisolone treatment was initiated. Anemia and submandibular gland swelling improved soon after prednisolone treatment was initiated. We report a rare case of IgG4-RD involving the bone marrow. FDG-PET/CT and bone marrow biopsy were useful for diagnosis in this case.

Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report.

A 40-year-old male developed refractory acute promyelocytic leukemia (APL) after various treatments including all-trans retinoic acid, tamibarotene, arsenic trioxide (As2O3), conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with tamibarotene and As2O3 as a single agent.

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy.

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

Clinical outcome of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein-Barr virus (EBV)-positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV-positive DLBCL is controversial. To compare the clinical outcome of EBV-positive and EBV-negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV-encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV-positive DLBCL patients. The median overall survival and progression-free survival times in patients with EBV-positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression-free survival could not be determined in EBV-negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV-positive DLBCL remains poor, even in the rituximab era.