Takashi Oyama

Age-Related EBV-Associated B-Cell Lymphoproliferative Disorders Constitute a Distinct Clinicopathologic Group: A Study of 96 Patients

Purpose: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs. To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Experimental Design: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected. We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Results: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). Conclusions: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.

Senile EBV+ B-cell lymphoproliferative disorders: A clinicopathologic study of 22 patients

Twenty-two Epstein-Barr virus-associated B-cell lymphoproliferative disorders (LPDs) without predisposing immunodeficiencies were evaluated clinically and pathologically. All patients were Japanese and negative for anti-human immunodeficiency virus antibody. They were all more than 60 years old with a median age of 75.5 years. Eighteen (82%) patients showed extranodal involvement. Biopsied specimens contained variable numbers of centroblasts, immunoblasts, and Reed-Sternberg-like giant cells often with necrosis and an angiocentric pattern. The 13 cases showing polymorphous composition and inflammatory background were categorized as polymorphic LPD subtype. The other nine cases contained diffuse proliferative lesions of large lymphoid cells and were categorized as large cell lymphoma subtype. Tumor cells expressed CD20 and/or CD79a, and in situ hybridization showed them to be associated with Epstein-Barr virus. LMP1 was detected in all cases and EBNA2 in seven. Eighteen patients initially received combination chemotherapy, and 12 achieved complete remission. However, six patients were refractory to chemotherapy and four patients with complete remission later relapsed. Eight of the 18 patients who received chemotherapy showed an aggressive disease course within a year after the diagnosis. There was a significant difference in prognosis between the group with polymorphic LPDs and the one with large cell lymphomas (p = 0.003). Although the disease profile of the 22 cases was analogous to that of immunodeficiency-associated B-cell LPDs, none of the patients showed evidence of underlying immunodeficiency-related diseases. These findings suggest that Epstein-Barr virus-associated LPD without immunodeficiency mainly occurs in elderly patients. Further investigations are needed to clarify the pathogenesis of this disease and to determine the optimal treatment strategy.

Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients.

Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder (aEBVLPD) is a disease group characterized by EBV-associated large B-cell lymphoma in elderly without predisposing immunodeficiency. In nearly one- third of cases, aEBVLPD occurs as a polymorphous subtype with reactive cell-rich components, bearing a morphologic similarity to classic Hodgkin lymphoma (cHL). The aim of this study was to clarify clinicopathologic differences between the polymorphic subtype of aEBVLPD (n = 34) and EBV(+) cHL (n = 108) in patients aged 50 years or older. Results showed that aEBVLPD was more closely associated with aggressive clinical parameters than cHL, with a higher age at onset (71 vs 63 years); lower male predominance (male-female ratio, 1.4 vs 3.3); and a higher rate of involvement of the skin (18% vs 2%), gastrointestinal tract (15% vs 4%), and lung (12% vs 2%). aEBVLPD was histopathologically characterized by a higher ratio of geographic necrosis, greater increase (> 30%) in cytotoxic T cells among background lymphocytes, higher positivity for CD20 and EBNA2, and absence of CD15 expression. As predicted by the clinical profile, aEBVLPD had a significantly poorer prognosis than EBV(+) cHL (P < .001). The polymorphous subtype of aEBVLPD constitutes an aggressive group with an immune response distinct from EBV(+) cHL, and requires the development of innovative therapeutic strategies.

Age‐related Epstein–Barr virus‐associated B‐cell lymphoproliferative disorders: Special references to lymphomas surrounding this newly recognized clinicopathologic disease

Epstein–Barr virus (EBV) is associated with some disease entities of malignant lymphomas, including Burkitt lymphoma, Hodgkin lymphoma, immunodeficiency‐associated lymphoproliferative disorders (LPD), and a part of diffuse large B‐cell lymphoma. We have recently identified a series of elderly patients with EBV‐associated (or EBV+) B‐cell LPD (B‐LPD) showing similarities in many respects to immunodeficiency‐associated LPD, although no evidence of underlying immunodeficiency was found. Therefore, the nosological category of senile or age‐related EBV+ B‐LPD has been proposed for those patients. A larger series of patients with this disease revealed that the relative ratios of such EBV+ B‐LPD to all diffuse large B‐cell lymphoma cases were higher with increasing with age, reaching a peak (20–30%) at ≥90 years of age, with a median of 71 years, providing additional evidence for our assertion that this disease may be related to immunological deterioration as a result of the aging process. This new disease entity is characterized pathologically by centroblasts, immunoblasts, and Hodgkin and Reed–Sternberg‐like giant cells with a varying degree of reactive components, often posing therapeutic and diagnostic problems for hematologists and pathologists, respectively. The aim of the present review is to briefly summarize the overall clinicopathological profile of this newly recognized age‐related (also called ‘senile’) EBV+ B‐LPD and EBV+ Hodgkin lymphoma for a practical diagnostic approach. (Cancer Sci 2008; 99: 1085–1091)

Age‐related EBV‐associated B‐cell lymphoproliferative disorders: Diagnostic approach to a newly recognized clinicopathological entity

EBV is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age‐related EBV‐associated B‐cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency‐associated ones, which may be associated with immune senescence in the elderly and which are now incorporated into the 2008 World Health Organization lymphoma classification as EBV‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly. This newly described disease is pathologically characterized by a proliferation of atypical large B cells including Reed–Sternberg‐like cells with reactive components, which pose a diagnostic problem for pathologists. Clinically, this disease may present with lymphadenopathy, and is often extranodal, frequently involving the skin, gastrointestinal tract, or lung. Onset is usually after the age of 50; the median patient age is 70–79 years, and incidence continues to increase with age, providing additional support to the nosological term of EBV+ DLBCL of the elderly. These patients have a worse prognosis than those with EBV‐negative DLBCL or EBV+ classical Hodgkin lymphoma (CHL). The aim of the present review was to summarize the clinicopathological profile of age‐related EBV+ LPD and EBV+ Hodgkin lymphoma to facilitate diagnostic approach.

Phase I study of inotuzumab ozogamicin (CMC-544) in Japanese patients with follicular lymphoma pretreated with rituximab-based therapy

Inotuzumab ozogamicin (CMC‐544), an antibody‐targeted chemotherapeutic agent composed of an anti‐CD22 antibody conjugated to calicheamicin, a potent cytotoxic antibiotic, specifically targets the CD22 antigen present in >90% of B‐lymphoid malignancies, rendering it useful for treating patients with B‐cell non‐Hodgkin lymphoma (B‐NHL). This phase I study evaluated the safety, tolerability, efficacy, and pharmacokinetics of inotuzumab ozogamicin in Japanese patients. Eligible patients had relapsed or refractory CD22‐positive B‐NHL without major organ dysfunction. Inotuzumab ozogamicin was administered intravenously once every 28 days (dose escalation: 1.3 and 1.8 mg/m2). All 13 patients had follicular lymphoma, were previously treated with ≥1 rituximab‐alone or rituximab‐containing chemotherapy, and were enrolled into two dose cohorts (1.3 mg/m2, three patients; 1.8 mg/m2, 10 patients). No patient had dose‐limiting toxicities, and the maximum tolerated dose, previously determined in non‐Japanese patients (1.8 mg/m2), was confirmed. Drug‐related adverse events (AEs) included thrombocytopenia (100%), leukopenia (92%), lymphopenia (85%), neutropenia (85%), elevated AST (85%), anorexia (85%), and nausea (77%). Grade 3/4 drug‐related AEs in ≥15% patients were thrombocytopenia (54%), lymphopenia (31%), neutropenia (31%), and leukopenia (15%). The AUC and Cmax of inotuzumab ozogamicin increased dose‐dependently with pharmacokinetic profiles similar to non‐Japanese. Seven patients had complete response (CR, 54%) including unconfirmed CR, four patients had partial response (31%), and two patients had stable disease (15%). The overall response rate was 85% (11/13). Inotuzumab ozogamicin was well tolerated at doses up to 1.8 mg/m2 and showed preliminary evidence of activity in relapsed or refractory follicular lymphoma pretreated with rituximab‐containing therapy, warranting further investigations. This trial was registered in ClinicalTrials.gov (NCT00717925). (Cancer Sci 2010)

CD56/NCAM-Positive Langerhans Cell Sarcoma: A Clinicopathologic Study of 4 Cases

This report concerns the clinicopathologic features of 4 patients with CD56/neural cell adhesion molecule (NCAM)-positive Langerhans cell sarcoma (LCS). Three of the patients were elderly, between 59 and 62 years of age at presentation, and the other was 35 years old. The presenting symptoms included fever, bone pain, and weakness. The patients shared some clinical findings, such as multiorgan involvement of lymph nodes, skin, lung, bone marrow, and spleen. LCS carries a poor prognosis, and 3 of the patients died of the disease within several years of presentation despite multiagent chemotherapy and radiotherapy. Of special interest is that all of the cases showed CD56 expression on the tumor cells in addition to expression of CD1a, S100β, and langerin, the presence of which suggests derivation from Langerhans cells. For control, CD56 was also examined in 8 cases of Langerhans cell histiocytosis (LCH), a single-system unifocal or multifocal disease, and the results of staining of the tumor cells were negative. Our findings indicated that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasms, although it is often difficult to draw a definite morphologically-based distinction between LCS and LCH.

Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder

Age‐related Epstein–Barr virus‐positive (EBV+) B‐cell lymphoproliferative disorder (ALPD) is a disease entity identified from a large‐scale re‐survey of cases diagnosed as diffuse large B‐cell lymphoma. ALPD is a group of EBV+ polymorphic B‐cell lymphoma typically seen in elderly patients. An age‐associated decline in host immunity against EBV might be partly responsible for the pathogenesis of ALPD. Histologically, ALPD is often characterized by a minor proportion of EBV‐encoded RNA‐positive tumor cells in a background of extensive cellular infiltration, similar to that of classical Hodgkins lymphoma. In contrast to Hodgkin and Reed–Sternberg cells, ALPD tumor cells are clearly positive for B cell markers CD20 and/or CD79a. Hodgkin and Reed–Sternberg cells produce various chemokines, including CCL17 and CCL22, that attract chemokine receptor CCR4‐expressing Th2 cells and regulatory T cells. Previously, we have shown that EBV‐immortalized B cells also produce CCL17 and CCL22 through latent membrane protein 1 (LMP1)‐mediated activation of nuclear factor κB. Here we examined expression of CCL17 and CCL22 in ALPD. ALPD tumor cells were often heterogeneous in size in accordance with the differential expression of EBV latent genes at the single cell level. LMP1‐expressing tumor cells were typically large in size and selectively positive for CCL17 and CCL22. CCR4+ cells and forkhead box protein 3+ regulatory T cells were abundantly present, and the majority of forkhead box protein 3+ cells were CCR4+. Collectively, our data show production of CCL17 and CCL22 by LMP1+ large‐sized tumor cells and accumulation of CCR4‐expressing cells including regulatory T cells in ALPD. (Cancer Sci 2008; 99: 296–302)

Plasmablastic lymphoma of the elderly: a clinicopathological comparison with age-related Epstein–Barr virus-associated B cell lymphoproliferative disorder

Liu F, Asano N, Tatematsu A, Oyama T, Kitamura K, Suzuki K, Yamamoto K, Sakamoto N, Taniwaki M, Kinoshita T & Nakamura S 
(2012) Histopathology
Plasmablastic lymphoma of the elderly: a clinicopathological comparison with age‐related Epstein–Barr virus‐associated B cell lymphoproliferative disorder

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma

Patients with follicular lymphoma (FL), where position 158 of FcγR‐IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F‐carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F‐carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody‐dependent cell‐mediated cytotoxicity. This dose‐escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20‐positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m2 weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F‐carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose‐limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F‐carriers. Further investigation of FL is warranted. (Cancer Sci 2011; 102: 432–438)