Chiyuki Kishimori

The novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in diffuse large B-cell lymphoma

An 82-year-old woman presented with generalized lymphadenopathy and skin involvement. Lymph node biopsy revealed diffuse large B-cell lymphoma with a high proliferation index. G-banding and fluorescence in situ hybridization showed a hypertetraploid karyotype with two copies of t(8;22)(q24;q11), generating the fusion of MYC and the immunoglobulin λ chain gene (IGL), and two copies of the novel immunoglobulin heavy chain gene (IGH) translocation, t(14;15)(q32;q24). A long-distance inverse polymerase chain reaction (PCR) using nested primer combinations designed for each constant gene of IGH showed that Cγ4 was juxtaposed to the downstream sequence of the BCL2A1 (BCL2-related protein A1) gene through the Sγ4 switch region. As a result of t(14;15)(q32;q24), BCL2A1 and IGH Sγ4-Cγ4 were aligned in the same transcriptional orientation at a distance of 64 kb. Reverse transcriptase-mediated PCR showed high BCL2A1 mRNA levels in a lymphoma specimen. Since BCL2A1, mapped at 15q24.3 or 15q25.1, encodes a protein that is an anti-apoptotic member of the BCL2 protein family, we herein described the novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in which BCL2A1 is considered to play a role equivalent to that of BCL2 in the most frequent double-hit, MYC/BCL2.

A rare MYC/BCL3 double-translocation and protein-expression in a diffuse large B-cell lymphoma

The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, published in 2017, proposed the category high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements [1]...

Pulmonary extranodal marginal zone lymphoma that presented with macroglobulinemia and marked plasmacytic cell proliferation carrying the t(14;18)(q32;q21)/ MALT1 -immunoglobulin heavy-chain fusion gene in pleural fluid

An 80-year-old man presented with the accumulation of pleural fluid in the right thoracic cavity. Serum electrophoresis revealed an M-component and immunofixation confirmed IgM/λ. The level of IgM was 1,526 mg/dL. Imaging studies showed an infiltrative condition of the ipsilateral lung parenchyma. The fluid contained abundant neoplastic cells with the morphological and immunophenotypic features of plasma cells, which expressed IgM/λ monoclonal immunoglobulins on the cell surface and in the cytoplasm. The karyotype was 48,XY,+3,add(9)(p13),+12,add(14)(q32),del(16)(q22),−18,+mar, and a series of fluorescence in situ hybridization studies demonstrated that the add(14) chromosome represented der(14)t(14;18)(q32;q21), at which the MALT1-immunoglobulin heavy-chain (IGH) fusion gene was localized. A long-distance polymerase chain reaction amplified the fragment encompassing the two genes, showing that the junction occurred at the J6 segment of IGH and 3.7-kb upstream of the MALT1 breakpoint cluster. We propose that this case represents an extreme form of the plasmacytic differentiation of extranodal marginal zone lymphoma that developed in the lung.

Acute basophilic leukemia associated with the t(16;21)(p11;q22)/FUS-ERG fusion gene

We herein report a rare case of acute basophilic leukemia with t(16;21)(p11;q22) generating the FUS‐ERG fusion gene. The basophilic nature of leukemia blasts was demonstrated by cytomorphology, toluidine blue metachromasia, mature basophil‐associated antigen expression, and characteristic granules under electron microscopy. The molecular link between t(16;21)/FUS‐ERG and basophilic differentiation remains unclear.

Cytogenetic evidence for the clonal hematopoietic cell origin of alveolar macrophages in myelodysplastic syndrome-associated pulmonary alveolar proteinosis

Dear Editor, Three major categories of pulmonary alveolar proteinosis (PAP) have been recognized: congenital form due to mutations in the genes for surfactant proteins or granulocyte macrophagecolony stimulating factor (GM-CSF) receptor, autoimmune PAP due to GM-CSF antibodies, and secondary PAP associated with heterogeneous conditions [1]. In a Japanese cohort of 404 PAP cases, 35 were associated with hematological disorders, including myelodysplastic syndrome (MDS) in 26 and other myeloid/lymphoid neoplasms in eight [2]. We previously described a 58-year-old female patient with the refractory cytopenia with multilineage dysplasia subtype of MDS [3]. Cytogenetic analysis of bone marrow cells revealed tandem triplication of the long arm of chromosome 1 [trp(1q)] as the sole cytogenetic abnormality [karyotype: 46,XX,trp(1)(q21q32)]. Fluorescence in situ hybridization (FISH) using a probe for the PBX1 (pre-B-cell leukemia homeobox 1) gene localized at 1q23 confirmed trp(1q) in both metaphase and interphase nuclei (Fig. 1a). The patient initially presented with prolonged productive coughing. Chest X-rays showed progressive infiltrates in both lungs, and computed tomography (CT) revealed patchy ground-glass opacification with thickened interlobular septa, predominantly in the lower lungs. The level of Kerbs von Lungren 6 antigen (KL-6), which is a biomarker of PAP and correlates with disease severity [4], was 3313U/mL (reference range, < 500 U/mL). Anti–GM-CSF autoantibody was negative. To confirm the association of PAP, we obtained bronchoalveolar lavage (BAL) fluids, showing a milky appearance and containing 660 cells per microliter in addition to globular materials with an amorphous structure (Fig. 1b) [1, 5, 6]. The cell differential was 0.5% neutrophils, 2.5% eosinophils, 53.5% lymphocytes, and 43.5% macrophages, and the macrophages had abundant foamy cytoplasm (Fig. 1b) [1]. FISH with the Vysis LSI TCF3/PBX1 dual color, dual fusion probe revealed that macrophage nuclei were labeled with four red (PBX1) signals, three of which were localized, and two green (TCF3, transcription factor 3 at 19p13.3) signals, while those of lymphocytes showed a two-red and two-green signal pattern (Fig. 1c–f). The patient underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-identical unrelated donor. The course was uneventful and donor-type hematopoiesis was promptly confirmed. CT 8 months after allo-HSCT revealed the improvement of pulmonary infiltrates, and the level of KL-6 had normalized. Unfortunately, she died of gastric cancer 18 months after transplant. We found trp(1q) in bone marrow cells and alveolar macrophages in common, indicating that PAP and MDS did not coincidently occur but were closely related disorders of clonal hematopoietic cell origin. The potential linkage between MDS and PAP is that alveolar macrophages derived from the MDS clone differentiate and proliferate locally and replace the normal macrophages, and, as MDS-clone– * Hitoshi Ohno hohno@tenriyorozu.jp