Junichi Kiyasu

Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma

Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1(+) DLBCL. We performed PD-L1/PAX5 double immunostaining in 1253 DLBCL biopsy samples and established a new definition of PD-L1(+) DLBCL. We also defined the criteria for microenvironmental PD-L1(+) (mPD-L1(+)) DLBCL (ie, PD-L1(-) DLBCL in which PD-L1(+) nonmalignant cells are abundant in the tumor microenvironment). Of the 273 patients whose clinical information was available, quantitative analysis of PD-1(+) tumor-infiltrating lymphocytes (TILs) was performed. The prevalence rates of PD-L1(+) and mPD-L1(+) DLBCL were 11% and 15.3%, respectively. Both PD-L1(+) and mPD-L1(+) DLBCL were significantly associated with non-germinal center B-cell (GCB) type and Epstein-Barr virus positivity. The number of PD-1(+) TILs was significantly higher in GCB-type tumors and lower in mPD-L1(-) and PD-L1(+) DLBCL. Patients with PD-L1(+) DLBCL had inferior overall survival (OS) compared with that in patients with PD-L1(-) DLBCL (P = .0009). In contrast, there was no significant difference in OS between mPD-L1(+) and mPD-L1(-) DLBCL (P = .31). The expression of PD-L1 maintained prognostic value for OS in multivariate analysis (P = .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1(+) DLBCL. Immunotherapy targeting the PD-1/PD-L1 pathway should be considered in this distinct DLBCL subgroup.

Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein–Barr virus, and clonality are important predictors of disease progression and regression

Patients with rheumatoid arthritis (RA) may develop lymphoproliferative disorders (RA‐LPD). Immunosuppressive states due to methotrexate (MTX) and Epstein–Barr virus (EBV) reactivation have been regarded as causes. Sometimes spontaneous regression occurs after withdrawal of MTX. The objective of this study was to identify factors predictive of relapse and survival in patients with RA‐LPD, and spontaneous regression in patients with RA‐LPD treated with MTX (MTX‐LPD).

Ratio of M2 macrophage expression is closely associated with poor prognosis for Angioimmunoblastic T-cell lymphoma (AITL)

Angioimmunoblastic T‐cell lymphoma (AITL) is a peripheral T‐cell lymphoma characterized by systemic disease with polymorphous infiltrate including macrophages. Although many studies of tumor‐associated macrophage (TAM) populations in various malignant tumors have been published, only a few have dealt with activation of macrophage phenotypes such as M1 and M2 in tumor tissue. Because M2 macrophages highly express CD163, we suspected that CD163 may be a useful marker for identification of activation of macrophage phenotypes in AITL. We performed a retrospective study of immunohistochemical expression using two markers for macrophages [CD68 (PG‐M1), CD163] and of the correlation of these expressions with overall survival of 42 AITL patients. The number of CD68‐positive cells in AITL tissues did not correlate with overall survival (P= 0.59), whereas the number of CD163‐positive cells and overall survival correlated to some extent (P= 0.08). Meanwhile, a higher ratio of CD163‐positive to CD68‐positive cells in AITL significantly correlated with worse overall survival (P= 0.036). Considering that this ratio reflects the proportion of macrophages polarized to the M2 phenotype, our findings indicate that activation of macrophages towards the M2 phenotype correlates with worse prognosis. Our findings indicate that the ratio of M2 macrophages expressed may be a useful marker for prognosis of AITL.

PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma.

Programmed cell death ligand 1 (PD-L1) is expressed on both tumor and tumor-infiltrating nonmalignant cells in lymphoid malignancies. The programmed cell death 1 (PD-1)/PD-L1 pathway suppresses host antitumor responses, although little is known about the significance of PD-1/PD-L1 expression in the tumor microenvironment. To investigate the clinicopathological impact of PD-L1 expression in adult T-cell leukemia/lymphoma (ATLL), we performed PD-L1 immunostaining in 135 ATLL biopsy samples. We observed 2 main groups: 1 had clear PD-L1 expression in lymphoma cells (nPD-L1(+), 7.4% of patients), and the other showed minimal expression in lymphoma cells (nPD-L1(-), 92.6%). Within the nPD-L1(-) group, 2 subsets emerged: the first displayed abundant PD-L1 expression in nonmalignant stromal cells of the tumor microenvironment (miPD-L1(+), 58.5%) and the second group did not express PD-L1 in any cell (PD-L1(-), 34.1%). nPD-L1(+) ATLL (median survival time [MST] 7.5 months, 95% CI [0.4-22.3]) had inferior overall survival (OS) compared with nPD-L1(-) ATLL (MST 14.5 months, 95% CI [10.1-20.0]) (P = .0085). Among nPD-L1(-) ATLL, miPD-L1(+) ATLL (MST 18.6 months, 95% CI [11.0-38.5]) showed superior OS compared with PD-L1(-) ATLL (MST 10.2 months, 95% CI [8.0-14.7]) (P = .0029). The expression of nPD-L1 and miPD-L1 maintained prognostic value for OS in multivariate analysis (P = .0322 and P = .0014, respectively). This is the first report describing the clinicopathological features and outcomes of PD-L1 expression in ATLL. More detailed studies will disclose clinical and biological significance of PD-L1 expression in ATLL.

Clinicopathological analysis of a composite lymphoma containing both T- and B-cell lymphomas

Composite lymphomas (CLs) have been reported in 1–4.7% of all lymphomas, however, CLs containing both T‐ and B‐cell lymphomas (CTBLs) are very rare. Here, we examined the clinical and pathological features of 29 CTBLs. These CTBLs included 21 patients with angioimmunoblastic T‐cell lymphoma (AITL) and diffuse large B‐cell lymphoma (DLBCL), two with adult T‐cell leukemia/lymphoma and DLBCL, one with AITL and Follicular lymphoma, one with Lennert lymphoma and DLBCL, one with subcutaneous panniculitis‐like T‐cell lymphoma and DLBCL, one with peripheral T‐cell lymphoma (PTCL) and DLBCL, one with cutaneous T‐cell lymphoma and DLBCL, and one with PTCL and chronic lymphocytic leukemia. Eighteen of 27 patients (67%) were shown to be Epstein‐Barr virus (EBV)‐encoded RNA‐positive in their B‐cell lymphoma component. T‐cell and B‐cell clonality were confirmed by flow cytometry, Southern blot analysis, and/or polymerase chain reaction (PCR). Using Southern blot analysis, clonal immunoglobulin heavy chain (IgH) and T‐cell receptor (TCR) rearrangements were detected in 11 of 21 and 15 of 24 cases, respectively. Using PCR analysis, clonal IgH and TCR rearrangements were detected in 7 of 8 and 7 of 7 Southern blot‐negative cases, respectively. Our results suggested that PCR analysis was useful in diagnosing CTBL.

Clinicopathological features and prognostic significance of CXCL12 in blastic plasmacytoid dendritic cell neoplasm

BACKGROUND Blastic plasmacytoid dendritic cell neoplasm (BPDC) is a rare hematologic neoplasm, which almost always involves the skin and shows poor prognosis. OBJECTIVE The aim of our study was to enhance BPDC diagnosis and indications for prognosis. METHODS This study involved 26 patients with BPDC. To investigate the histogenesis of BPDC, we reviewed the clinical features and stained markers of various hematopoietic lineages, chemokines, and their receptors. RESULTS Bone-marrow infiltration was detected in 13 of the 19 cases examined and leukemic changes in 18. Complete remission was achieved in 14 cases, but more than half of the patients showed recurrence within a short time, and 14 patients died of the disease after 1 to 25 months (mean 8.5 months). Positivity for CD123 was detected in 18 of 24 cases and for T-cell leukemia 1 in 18 of 22 cases. Of the chemokines and their receptors, 8 of 15 skin biopsy specimens proved to be positive for CXCL12. Leukemic change subsequent to skin lesions occurred in 7 of 8 CXCL12-positive cases (87.5%) and in 3 of 6 CXCL12-negative cases (50%). Seven of the 8 CXCL12-positive patients (87.5%) and two of the 6 CXCL12-negative patients (33.3%) have died, whereas one of 8 CXCL12-positive patients (12.5%) and 4 of 6 CXCL12-negative patients (66.7%) remain alive. LIMITATIONS The number of patients was limited. CONCLUSIONS We speculate that the presence of CXCL12-positive cells in the skin may be associated with leukemic change and a poor prognosis.

Regression of rectal mucosa‐associated lymphoid tissue (MALT) lymphoma after antibiotic treatments

Only a few reports have described regression of rectal mucosa‐associated lymphoid tissue (MALT) lymphoma after antibiotic treatment are generally found to be successful for gastric tumors. We examined eight rectal MALT lymphomas treated with antibiotic treatments to determine whether they regressed after treatment. We also discuss the relationship between rectal MALT lymphomas and MALT1 gene genetic abnormalities. Eight patients who had undergone antibiotic treatments were followed up with colonoscopy after initiation of the treatment. In five of the eight cases (63%) endoscopic examination showed that the rectal tumor had disappeared, which was confirmed histologically. Polymerase chain reaction for immunoglobulin heavy chain identified a monoclonal band in seven of eight cases (88%). Of the eight cases analyzed with fluorescence in situ hybridization (FISH) for MALT1 translocation, two demonstrated MALT1 gene genetic abnormality. These cases tended to be resistant to antibiotic treatment. Investigation and analysis of a large number of rectal MALT lymphomas are needed to establish suitable standards for antibiotic treatment.

Clinicopathologic analysis of peripheral T-cell lymphoma, follicular variant, and comparison with angioimmunoblastic T-cell lymphoma: Bcl-6 expression might affect progression between these disorders.

We examined clinicopathologic findings in 17 cases of peripheral T-cell lymphoma, follicular variant (f-PTCL), and compared these findings with angioimmunoblastic T-cell lymphoma (AITL) to determine whether they were identical to the spectrum of changes seen in AITL and how each of the findings in f-PTCL were related to the characteristics of AITL. Almost all f-PTCL cases showed pathologic characteristics of AITL and immunohistochemical positivities in lymphoma cells for CD4, CD10, Bcl-6, PD-1, and CXCL13. Except for pathologic characteristics, clinicopathologic findings in f-PTCL had few significant differences from AITL. The positive rate for Bcl-6 expression in neoplastic cells was significantly associated with the frequency of polymorphic infiltrates, vascular proliferation, B-immunoblasts, clear cells, Epstein-Barr virus-positive lymphocytes, hepatosplenomegaly, and skin rash. Our study confirmed the continuity between f-PTCL and AITL. Moreover, Bcl-6 expression in f-PTCL was statistically associated with the characteristics of AITL.

Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry

X‐linked lymphoproliferative syndrome (XLP) is a rare immunodeficiency with extreme vulnerability to Epstein‐Barr virus (EBV) infection. It presents with fatal infectious mononucleosis, lymphoproliferative disorder, or dysgammaglobulinemia. The majority of affected males have mutations in the SH2D1A/SLAM‐associated protein (SAP) gene. We previously generated an antihuman SAP monoclonal antibody (KST‐3) for a flow cytometric assay and described the activation of T cells to be necessary for the flow cytometric assessment of the SAP expression using an FITC‐conjugated secondary antibody.

Administration of an anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab, before allogeneic bone marrow transplantation for adult T-cell leukemia/lymphoma.

Administration of an anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab, before allogeneic bone marrow transplantation for adult T-cell leukemia/lymphoma