In 2017, the revised World Health Organization was published. Regarding myeloproliferative neoplasms, histological findings of bone marrow biopsy is becoming more important for diagnosis. This article highlights particularly the morphology of megakaryocytes and evaluation of myelofibrosis for pathological diagnosis, and immunohistochemistry which can detect somatic mutation.
Myeloma is characterized by the neoplastic proliferation of monoclonal plasma cells. A diagnosis of myeloma is based on the criteria proposed by the International Myeloma Working Group and the pathological findings.
Myeloma cells are classified into four types: mature, immature, pleomorphic, and plasmablastic. There are three patterns in which myeloma infiltrates bone marrow - nodular, interstitial, and diffuse. Dutcher bodies are highly specific to neoplastic myeloma cells. On immunohistochemical staining, the specificity of CD138 is high for plasma cells. As a clear image is often not obtained from the immunohistochemical staining of the immunoglobulin light chain, in situ hybridization is recommended. Abnormal expression of CD56 is seen in 70-80% of cases by flow cytometry analysis. CD56 expression definitively indicates myeloma, suggesting its high diagnostic value. Evaluation of the infiltration pattern, monoclonality, and abnormal antigen expression of plasma cells is more important than the plasmocytic ratio to determine whether a case is reactive or neoplastic.
Multiple gene abnormalities function in the onset and progression of myeloma. In our department, we analyze CCND1, FGFR3, MAF, and del (17p13) by FISH for all myeloma cases. None of the cases with genetic abnormalities were recognized by G-banding. Therefore, FISH is more effective than G-banding for the evaluation of genetic abnormalities in myeloma.
Bone marrow failure (BMF) is a rare but life-threatening disorder that usually manifests as (pan)cytopenia. BMF can be caused by a variety of diseases, but inherited BMF (IBMF) syndromes are a clinically important cause, especially in children. IBMF syndromes are a heterogeneous group of genetic disorders characterized by BMF, physical abnormalities, and predisposition to malignancy. An accurate diagnosis is critical, as disease-specific management, surveillance, and genetic counselling are required for each patient. The major differential diagnoses of IBMF syndromes are acquired aplastic anemia (AA) and refractory cytopenia of childhood (RCC). These diseases have overlapping features, such as BM hypocellularity and/or dysplastic changes, which make the differential diagnosis challenging. RCC has been defined as a histomorphologically distinct entity. Therefore, understanding the BM histopathology of these diseases is essential for the differential diagnosis. However, the BM histopathological features have not been characterized in detail, as descriptions of BM histopathology are very limited due to the rarity of the diseases. This review provides a detailed description of the BM histopathology in cases of RCC, AA, and the four most common IBMF syndromes: Fanconi anemia (FA), dysketatosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). An overview, including the clinical features and diagnosis, is also provided.
Macrophages play a central role in the immune response, and their diverse functions are attributed to the spectrum of their functional states. To elucidate molecules involved in modulating the balance between the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine TNF-α, we conducted genome-wide siRNA screening. First, we established an siRNA screening system using mouse bone marrow-derived macrophages, which are a suitable model for studying functional states of macrophages in vitro. In the primary screen and the subsequent reproducibility assay, 112 siRNA pools demonstrated enhancement of IL-10 production and 497 siRNA pools suppressed IL-10 production. After a deconvolution assay for IL-10-up-regulating siRNA pools, 8 genes were identified as IL-10 repressors, including Cnot1 and Rc3h1, components of the CCR4-NOT complex known to degrade cytokine mRNAs. On the other hand, siRNA pools targeting ribosomal proteins were frequently found among those that down-regulated IL-10 production and up-regulated TNF-α production. Four pools were assayed using deconvoluted siRNAs and identified as high-confidence hits. Thus, we found that the genome-wide knockdown of 19 ribosomal proteins resulted in decreased IL-10 and increased TNF-α production.
Recent progress in anti-tumor immunotherapy has focused on the significance of the tumor microenvironment in tumor progression and resistance to chemo/radio-therapy. Myeloid cells such as macrophages are predominant stromal components in hematological malignancies. In the present study, we investigated the regulation of programmed death-1 (PD-1) ligand expression in primary central nervous system lymphoma (PCNSL) using PCNSL cell lines and human monocyte-derived macrophages. TK PCNSL cell line-derived soluble factors induced overexpression of PD-1 ligands, indoleamine 2,3-dioxygenase (IDO1), and several other cytokines in macrophages. The expression of PD-1 ligands was dependent on the activation of signal transducer and activator of transcription 3. PD-L1 and IDO1 were overexpressed by macrophage/microglia in PCNSL tissues, and gene expression profiling indicated that IDO1 expression was positively correlated with the expression of macrophage and lymphocyte markers. Macrophage-derived factors did not influence the proliferation or chemo-sensitivity of cell lines. These data suggest that the expression of immunosuppressive molecules, including PD-1 ligands and IDO1, by macrophage/microglia may be involved in immune evasion of lymphoma cells.
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a new clinical entity that was reclassified from enteropathy-associated T-cell lymphoma in the 2016 WHO classification. An 83-year-old man with fever and diarrhea was referred to our hospital because of free air in the abdominal cavity and wall thickening of the large intestine on CT. Colonofiberscopic examination revealed mucosal edema and multiple ulcers at the sigmoid colon, splenic flexure, and transverse colon. Histopathological examination of the mucosal biopsy specimen demonstrated dense infiltration of small lymphocytes with nuclear atypia, some of which exhibited intraepithelial invasion. Immunohistologically, these lymphocytes were positive for CD3, CD56, and perforin. Regarding CD3 expression, the antigen was found to only be expressed in the cytoplasm and not on the surface membrane on flow cytometric analysis. PCR examination of the T-cell receptor (TCR) gene revealed monoclonal gene rearrangements of TCR-γ and TCR-β. Based on these findings, a diagnosis of colonal MEITL with cyCD3 expression at Lugano clinical stage 1 was made. After conservative management of the peritonitis, we treated the patient with CHOP and DeVIC regimens, but he developed progressive disease and died. The cyCD3 expression in MEITL may be novel, suggesting a thymocyte origin of the tumor cells.