Journal of Clinical and Experimental Hematopathology最新文献

Primary central nervous system (CNS) lymphomas account for 1.9-3% of all brain tumors, with the majority being histologically classified as primary large B-cell lymphoma of the CNS (PCNS-LBCL). PCNS-LBCL is characterized by mature germinal center-exit B cells, and most cases of this phenotype are classified as activated B-cell-like phenotype according to gene expression profiling, or as non-germinal center B-cell-like phenotype (non-GCB type) according to Hans's algorithm. Genetically, PCNS-LBCL often shows mutations in MYD88^L265P and CD79B^Y196, and is similar to MCD or C5 in genetic subtypes. Therefore, we here investigated the clinicopathological and molecular characteristics of primary CNS B-cell lymphomas (PCNSBLs), focusing on the differences in the frequency of MYD88^L265P and CD79B^Y196 mutations, as well as the prognosis between GCB and non-GCB types. Forty-two patients with PCNSBLs were included in this study, with 12 (28.6%) classified as GCB type and 30 (71.4%) as non-GCB type. There were no significant differences between the two types in gender, tumor location, or frequency of MYD88^L265P and CD79B^Y196 mutations. Even after consideration of the confounding of age and the presence of R-MPV therapy, the GCB type PCNSBLs tended to exhibit better prognosis. Overall survival tended to be better in those with the GCB/MYD88^L265P mutation (-) group, followed by the GCB/MYD88^L265P mutation (+) group, and the non-GCB type. We speculate that Hans's algorithm and MYD88^L265P mutation may have potential prognostic value for PCNSBLs.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease unrelated to the Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8) infection. Presently, iMCD is classified into iMCD-IPL (idiopathic plasmacytic lymphadenopathy), iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis/renal insufficiency, and organomegaly), and iMCD-NOS (not otherwise specified). The most common treatment for iMCD is using IL-6 inhibitors; however, some patients resist IL-6 inhibitors, especially for iMCD-TAFRO/NOS. Nevertheless, since serum IL-6 levels are not significantly different between the iMCD-IPL and iMCD-TAFRO/NOS cases, cytokines other than IL-6 may be responsible for the differences in pathogenesis. Herein, we performed a transcriptome analysis of cytokine storm-related genes and examined the differences between iMCD-IPL and iMCD-TAFRO/NOS. The results demonstrated that counts per million of STAT2, IL1R1, IL1RAP, IL33, TAFAIP1, and VEGFA (P < 0.001); STAT3, JAK2, MAPK8, IL17RA, IL18, TAFAIP2, TAFAIP3, PDGFA, VEGFC, CXCL10, CCL4, and CXCL13 (P < 0.01); and STAT1, STAT6, JAK1, MAPK1, MAPK3, MAPK6, MAPK7, MAPK9, MAPK10, MAPK11, MAPK12, MAPK14, NFKB1, NFKBIA, NFKBIB, NFKBIZ, MTOR, IL10RB, IL12RB2, IL18BP, TAFAIP6, TNFAIP8L1, TNFAIP8L3, CSF2RBP1, PDGFB, PDGFC, and CXCL9 (P < 0.05) were significantly increased in iMCD-TAFRO/NOS. Particularly, upregulated IL33 expression was demonstrated for the first time in iMCD-TAFRO/NOS. Thus, inflammatory signaling, such as JAK-STAT and MAPK, may be enhanced in iMCD-TAFRO/NOS and may be a cytokine storm.

Juvenile xanthogranuloma (JXG) is a rare benign non-Langerhans cell histiocytosis that usually occurs in cutaneous lesions on the head, neck, or upper trunk of neonates and young children. Intramuscular JXG, which invades muscle tissue, accounts for only 0.6% of all JXGs and mostly occurs in the skeletal muscles of the extremities or trunk. A 5-month-old girl was referred to our hospital. At the age of 3 months, she presented with a slow-growing lump on her left thigh. Magnetic resonance imaging (MRI) showed a 22 × 19 × 18 mm oval mass in her left thigh. First, needle biopsy results suggested deep JXG or myeloid sarcoma. Therefore, marginal resection was performed. Intraoperatively, the tumor adhered to the left tensor fasciae latae muscle and was resected together. Histopathological examination revealed a diffuse monotonous sheet-like proliferation of mononuclear histiocyte-like cells with pale, eosinophilic, foamy cytoplasm with a background of muscle and fatty tissue. Minimal mitotic figures and no nuclear atypia or multinucleated giant cells were observed. Immunohistochemical analysis was positive for CD68 (KP-1) and CD163; weakly positive for lysozyme; and negative for CD1a, S100, myeloperoxidase, and CD34. No blast proliferation was observed in the bone marrow. The patient was diagnosed with deep JXG and scheduled for periodic physical examination and MRI. Despite positive margins, the patient fared well without local recurrence 48 months after tumor removal. Understanding the unique pathology of deep JXG and detailed histological evaluation are important for decision-making.

Primary thyroid lymphoma is a rare type of cancer. Most cases involve large B-cell lymphomas (LBCLs), which largely show good prognoses. However, the reasons for this have not been understood. To identify the factors influencing the favorable clinical outcomes of thyroid LBCLs, clinicopathological and genetic analyses of 21 cases of thyroid LBCLs were performed, including immunohistochemistry, fluorescence in situ hybridization (FISH), and analysis for MYD88 mutations based on the World Health Organization Classification of Tumors, 5th Edition. The median age of the patients was 70 years (range, 54-80 years). Fifteen patients (71%) had limited-stage disease. The 5-year overall survival rate was 83% (95% confidence interval: 56%-94%). No instances of central nervous system (CNS) recurrence was observed. The series included 15 cases with diffuse LBCL not otherwise specified (DLBCLnos) and 6 cases with transformation of indolent BCLs (T-IBCLs). Immunohistochemistry subdivided DLBCLs into 12 germinal center B-cell (GCB) and 9 non-GCB subtypes. FISH analysis revealed split signals of MYC in 2/17 cases, MALT1 in 0/15 cases, and BCL6 in 3/15 cases. No MYD88 mutations were detected in any of the cases (0/21). The factors contributing to the favorable clinical course in thyroid LBCLs were a higher proportion of GCB phenotypes and the lack of MYD88 mutations in DLBCLnos and T-IBCLs. Even MYC-R cases showed better prognosis. Further studies involving a large series of LBCLs in extranodal organs are needed to expand on the findings of this study.

A 79-year-old Japanese woman presented with exertional dyspnea. She had cardiac tamponade and urgent pericardial drainage was performed. Pathological findings from the pericardial fluid revealed non-germinal center B-cell (non-GCB) pericardial large B-cell lymphoma (CD10^-, BCL6⁺, and MUM1⁺). Although a diagnosis of fluid overload-associated large B-cell lymphoma was considered, GCB nodal diffuse large B-cell lymphoma (CD10⁺, BCL6⁺, and MUM1⁺) was discovered through needle biopsy of the enlarged left axillary lymph node. Despite the two lymphomas exhibiting different expression levels of CD10, polymerase chain reaction assessing IgH gene rearrangement suggested a clonal relationship between them. Additionally, MYD88 L265P mutation was confirmed using Sanger sequencing in both samples, suggesting the MCD type. Our case highlights a discrepancy between the Hans' criteria and the gene expression profile-based cell of origin.

Cluster of Differentiation 54 (CD54), also known as intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. Although CD54 has been shown to be involved in cell-to-cell adhesion and proliferation of B-cell lymphoma cell lines, the clinical significance of its expression has not yet been elucidated. We analyzed Ki-67 indices, the expression status of CD54 and its receptor (CD11a), and the intercellular distance of tumor cells in 40 diffuse large B-cell lymphoma (DLBCL) cases with vascular invasion to analyze the association of cell adhesion and proliferation status. CD54 and CD11a were simultaneously expressed (double-positive) in extra/intravascular tumor cells in 14 (35%) of the cases. Histologically, lymphoma cells of the double positive cases exhibited significantly higher Ki-67 index in extravascular tumor cells than that in the intravascular ones, while no difference was observed in lymphoma cells of the non-double positive cases. The significantly shorter extravascular intercellular distance compared with the intravascular intercellular distance suggested the association between cell-cell adhesion mediated by CD54 and cell proliferation. We further confirmed that the treatment of the recombinant LFA1 (CD11a/CD18) showed the adhesion of human DLBCL-derived cell line HBL-2 to LFA1 and increased cell viability. These findings suggest that cell-to-cell adhesion via CD54 maintains the cell proliferative activity of a subset of DLBCL. This study provides a valuable foundation upon which further research may be conducted to determine detailed mechanisms of cell-to-cell-associated and adhesion-independent cell proliferation.

Reactivation of hepatitis viruses during chemotherapy can be problematic in the treatment of malignant lymphomas. However, studies on reactivation of chronic hepatitis C virus (HCV) infection are limited. A 43-year-old woman presented with generalized lymphadenopathy and multiple liver tumors, and she was diagnosed with follicular lymphoma (grade 3a; clinical stage IV). Chronic HCV infection was clinically diagnosed. Immunochemotherapy (ICT), including bendamustine and obinutuzumab, was initiated with close liver function monitoring without specific treatment for hepatitis C. However, liver dysfunction worsened 17 days after ICT initiation, and ICT was interrupted. HCV-RNA and transaminase levels continued to elevate. Liver biopsy results confirmed acute exacerbation of chronic hepatitis C. Direct active antiviral (DAA) therapy was started and effective. She has maintained a sustained virologic response since DAA therapy ended. With regard to lymphoma, complete metabolic response was maintained for 4 years without additional treatment. Physicians should be aware of HCV reactivation with hepatitis flare after ICT for lymphoma and consider the indication and timing of DAA therapy for hepatitis C in this setting.

Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.

A 78-year-old Japanese man presented to the emergency department with a sore throat and fever that worsened over 3 weeks. A tonsil biopsy led to the diagnosis of pleomorphic mantle cell lymphoma (MCL) that had infiltrated the right adrenal gland, inferior vena cava, and right atrium (RA). Although the patient's cardiac tumor had high mobility, his hemodynamic state was stable, and he did not present with fatal arrhythmia. Therefore, we first introduced chemotherapy. However, the patient developed recurrent pulmonary embolisms (PEs) and died after starting chemotherapy. An autopsy revealed that the MCL had invaded the large vessels, causing the PEs. Although the high mobility of cardiac tumors is known to increase the risk of PE in diffuse large B-cell lymphoma (DLBCL), optimal management of cardiac MCL remains to be elucidated owing to its rarity. To the best of our knowledge, this is the first report of cardiac MCL with posttreatment PE development in a Japanese patient. It is worth considering preventive surgery before treatment not only in DLBCL, but also in MCL based on the mobility of the cardiac tumors. Our case highlights the need for close communication between hematologists and cardiologists to treat cardiac MCL.