Kensaku Sato

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).

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.

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.

Comparison of CD20 expression in B-cell lymphoma between newly diagnosed, untreated cases and those after rituximab treatment

Few studies have statistically investigated reduced CD20 expression in B‐cell lymphoma after rituximab therapy and genomic mutation of CD20 associated with reduction. We examined CD20‐positive rate in follicular lymphoma (FL) and diffuse large B‐cell lymphoma (DLBCL) by flow cytometry (FCM) and immunohistochemical staining (IHS), comparing 138 cases after rituximab therapy with 360 initial, not yet treated cases. Sequence analysis of exons 3 to 8 of CD20 was performed on 22 cases with low CD20‐positive rate after rituximab treatment. The results showed a statistical correlation between CD20‐positive rate in FCM and IHS. By FCM, the CD20‐positive rate among post‐rituximab cases was significantly lower than among initial cases in DLBCL, non‐germinal center origin B‐cell type (average values [avg] 57.8 and 87.9, respectively) (P < 0.0001), FL2 (avg, 93.9; 103.2) (P = 0.0083), and FL3A (avg, 90.6; 100.7) (P = 0.033). Stratified analyses of post‐rituximab cases showed significantly lower CD20‐positive rate in cases that were resistant at the start of the treatment and cases with progressive disease during rituximab therapy before biopsy. Sequence analysis showed silent mutation of exon 4 (632 C/T) in seven cases, although this number was not statistically significant. These results suggest the influence of B‐lymphoma subtype and a therapeutic effect before biopsy on CD20 expression at relapse and contribute to a better therapeutic approach for relapse cases after rituximab therapy. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02307.x, 2012)

Small cell variant of mantle cell lymphoma is an indolent lymphoma characterized by bone marrow involvement, splenomegaly, and a low Ki-67 index

Mantle cell lymphoma (MCL) is recognized as a well‐defined B cell neoplasm characterized by overexpression of cyclin D1 (CCND1), with “classical” and “aggressive” variant subtypes. A small‐cell variant of MCL (small‐MCL), resembling small lymphocytic lymphoma/chronic lymphocytic lymphoma (CLL/SLL), has been added to the World Health Organization classification. However, to the best of our knowledge, there have been no studies focusing on this neoplasm. In the present study, we analyzed 15 cases of CCND1‐positive small‐MCL, including immunohistochemical analysis of Ki‐67 and CCND1 expression, and compared our findings with those of 151 cases of classical MCL. Morphologically, most small‐MCL showed a diffuse growth pattern (76.9%), whereas others featured a very thin mantle zone pattern resembling a reactive follicle (23.1%). Bone marrow involvement and splenomegaly occurred significantly more frequently in small‐MCL than in classical MCL (P < 0.05). Ki‐67 expression in small‐MCL was lower than in classical MCL (mean [±2 SD] 12.5 ± 17.3% and 25.2 ± 25.5%, respectively; P < 0.001), but there was no significant difference in CCND1 expression (P = 0.2445). The 5‐year survival rate in small‐MCL was 83.3%. Although there was no significant difference in outcome between small‐MCL and classical MCL (P = 0.287), only one small‐MCL patient died of the disease. Thus, small‐MCL constitutes a specific subset of indolent lymphoma with distinguishing features, possibly making a major contribution to the accuracy of therapeutic decisions. In addition, clinicians should be aware of the possible presence of small‐MCL to avoid making a misdiagnosis of follicular hyperplasia or CLL/SLL. (Cancer Sci 2011; 102: 1734–1741)

Mantle cell lymphoma shows three morphological evolutions of classical, intermediate, and aggressive forms, which occur in parallel with increased labeling index of cyclin D1 and Ki-67

(Cancer Sci 2010; 101: 806–814)

CD5-positive follicular lymphoma characterized by CD25, MUM1, low frequency of t(14;18) and poor prognosis

CD5‐positive follicular lymphoma (FL), although rare, has been described in a number of case reports. However, a statistically valid, clinicopathological comparison between CD5‐positive FL and CD5‐negative FL has never been performed because of its rarity. We statistically compared clinicopathological characteristics of 22 cases of CD5‐positive FL, diagnosed by immunohistochemistry, flow cytometry and morphological findings, with those of 62 cases of FL without CD5 expression (control cases). CD5‐positive FL patients showed a higher tendency of peripheral blood involvement (P = 0.076) and a higher frequency of CD25 expression (P = 0.0004) and MUM1 protein expression (P = 0.0008), and a lower frequency of t(14;18)(q32;q21) (P = 0.017). The overall survival (OS) curve of CD5‐positive FL was significantly worse than that of control cases (P = 0.0266), although progression‐free survival curves did not show a significant difference (P = 0.7899). Moreover, CD5 expression was shown to be an independent poor prognostic factor for OS in both univariate analysis [Hazard Ratio (HR), 3.63; P = 0.0464] and multivariate analysis (HR, 57.16; P = 0.0001). CD5‐positive FL showed different clinicopathological characteristics from FL lacking CD5 expression. These results suggest that CD5‐positive FL should be considered a different type of FL, and its clinicopathological management should be conducted differently.

Detection of Tax-specific CTLs in lymph nodes of adult T-cell leukemia/lymphoma patients and its association with Foxp3 positivity of regulatory T-cell function

Human T-cell lymphotropic virus type (HTLV)-1 Tax is a viral protein that has been reported to be important in the proliferation of adult T-cell leukemia/lymphoma (ATLL) cells and to be a target of HTLV-1-specific cytotoxic T lymphocytes (CTLs). However, it is not clear how Tax-specific CTLs behave in lymph nodes of ATLL patients. The present study analyzed the immunostaining of Tax-specific CTLs. Furthermore, ATLL tumor cells are known to be positive for forkhead box P3 (Foxp3)and to have a regulatory T (Treg)-cell-like function. The association between T-reg function and number and activity of Tax-specific CTLs was also investigated. A total of 15 ATLL lymphoma cases with human leukocyte antigen (HLA)-A24, for which Tax has a high affinity, were selected from the files of the Department of Pathology, School of Medicine, Kurume University (Kurume, Japan) using a polymerase chain reaction (PCR) method. Immunostaining was performed for cluster of differentiation (CD) 20, CD3, CD4, CD8, T-cell intracellular antigen-1 and Foxp3 in paraffin sections, and for Tax, interferon γ and HLA-A24 in frozen sections. In addition, the staining of Tax-specific CTLs (HLA-A24-restricted) was analyzed by MHC Dextramer® assay in frozen sections. In addition, the messenger RNA expression of Tax and HTLV-1 basic leucine zipper factor were also evaluated by reverse transcription-PCR. Immunohistochemical staining of Tax protein in lymphoma tissue revealed the presence of positive lymphoma cells ranging from 5 to 80%, and immunohistochemical staining of HLA-A24 revealed the presence of positive lymphoma cells ranging from 1 to 95%. The expression of Tax and HLA-A24 was downregulated by viral function. Foxp3, a marker for Treg cells, was expressed in 0–90% of cells. Several cases exhibited Tax-specific CTL (HLA-A24-restricted)-positive cells, and there was an inverse correlation between Tax-specific CTLs and Foxp3. However, neither Tax nor HLA-A24 expression was associated with CTL or Foxp3. Our study indicated the possibility that ATLL cells, which expressed Tax, target of CTL, evade the CTL-mediated immune control by expression of Foxp3 as a Treg function.

Frequent expression of gp46 in adult T‐cell leukemia/lymphoma: An immunohistochemical study of 40 cases

Adult T‐cell leukemia/lymphoma (ATLL) is a lymphoproliferative disease caused by human T‐cell lymphotropic virus type 1 (HTLV‐1) infection. HTLV‐1 is spread by cell‐to‐cell transmission via the gp46‐197 region, from Asp197 to Leu216, in the envelope protein gp46. A correlation exists between the prevalence and titer of the antibody recognizing the gp46‐197 region (anti‐gp46‐197 antibody) and the severity of ATLL. In the present study, immunohistochemical staining was performed on samples of paraffin embedded lymph nodes of three different histological types of ATLL (anaplastic large cell type, n = 10; pleomorphic type, n = 10; and Hodgkins‐like type, n = 10) from 30 cases and 10 cases of HTLV‐associated lymphadenitis. Of the three ATLL subtypes, gp46 expression was highest in the anaplastic large cell type, followed by the pleomorphic type and Hodgkins‐like type (mean: 53.4%, 34.9% and 16.0%, respectively; P= 0.0003). In HTLV‐1 associated lymphadenitis cases, gp46 positive cells were rarely seen (4.0%). These results suggest that gp46‐197 immunohistochemical staining can be a useful histological indicator for prediction of the aggressiveness of ATLL and prognosis for ATLL patients.

Epidemiology and secular trends of malignant lymphoma in Japan: Analysis of 9426 cases according to the World Health Organization classification

This study provides an overview of the epidemiology and secular trends of malignant lymphoma in Japan. Using data from clinics and hospitals throughout Japan, we analyzed 9426 cases of malignant lymphoma diagnosed in 2007‐2014. We show that the proportion of follicular lymphoma and methotrexate‐associated lymphoproliferative disorder increased during this time, as did the onset age for follicular lymphoma and diffuse large B‐cell lymphoma. Significant increases in onset age for follicular lymphoma and diffuse large B‐cell lymphoma were observed in both men and women (all P values <0.0001 except for P = 0.0448 for the latter disease in women). Further studies are required to determine the reasons for the higher proportion of and onset age for these lymphomas. Additionally, we believe that continued observation of these trends is necessary.