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Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) and severe mosquito bite allergy (SMBA) are both cutaneous forms of Epstein-Barr virus (EBV)-associated T/natural killer (NK) cell LPDs and are closely related to chronic active EBV disease (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). HV-LPD is further divided into classic HV, a benign subtype mediated by EBV-positive γδT cells, and systemic HV, another life-threatening subtype mainly associated with EBV-positive αβT or γδT cells. The vast majority of patients with SMBA have increased numbers of EBV-infected NK cells in the blood. Clinical symptoms of HV-LPD and SMBA often overlap in the same patient and may progress to more serious disease conditions equivalent to the systemic form of CAEBV. To define the disease spectrum of HV-LPD and SMBA, we propose the diagnostic criteria and the determination criteria for disease severity. The proposed diagnostic criteria are consistent with those for CAEBV and EBV-HLH in the guidelines for the management for CAEBV and related disorders 2023., (© 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

A 55-year old female patient was treated with methotrexate (MTX) and infliximab (IFX) for rheumatoid arthritis (RA). She experienced unknown fever, generalized lymphadenopathy, and liver tumors. Histological examination of the inguinal lymph node and a liver tumor resulted in the pathological diagnosis of classic Hodgkin lymphoma, with many Reed-Sternberg cells with the positivity of Epstein-Barr virus (EBV). She was diagnosed with MTX-related lymphoproliferative disorders (MTX-LPDs). She received chemotherapy after the cessation of MTX and IFX and achieved complete remission. RA showed recurrence after a while, and she was treated with steroids or other drugs. Six years after the chemotherapy, she experienced low-grade fever and anorexia. Whole computed tomography images showed an appendix tumor and enlargement of the surrounding lymph nodes. Appendectomy with the radical lymph nodes dissection was performed. The pathological diagnosis was diffuse large B-cell lymphoma, resulting in the clinical diagnosis of the relapse of MTX-LPD. EBV was negative at this point. The pathological findings of MTX-LPD may change at relapse; thus, biopsy should be considered when the relapse of MTX-LPD is suggested.

Lymphoproliferative disorder (LPD) can occur in patients with inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). On rare occasions, patients with IBD develop myeloid neoplasms; however, the frequency and clinicopathological features of IBD-associated lymphoid and myeloid proliferative disorder (LMPD) in Japanese patients are still unclear. In this study, we reviewed 2474 Japanese patients with IBD and found that LMPD occurred in 12 (0.5%) patients with UC (n = 7) or CD (n = 5). Together with an additional 3 cases, we analyzed a total of 15 cases of LMPD for clinicopathological and histological features. Based on the status of using immunosuppressants such as biologics and immunomodulators, Epstein-Barr virus (EBV) infection, and histopathology, the 15 cases were classified into Group I (high-grade LPD; n = 7), Group II (low-grade LPD; n = 5), and Group III (myeloid neoplasms; n = 3). Most patients in Group I were undergoing strong immunosuppressive therapy, and the LPD lesions corresponded to high-grade B-cell or T cell/natural killer cell lymphoma often with EBV infection. Discontinuation of immunosuppressive drugs alone did not resolve these LPDs; Group I patients required chemotherapy, and eventually 4 of them (57%) died of the tumor. Most cases in Group II were low-grade B-cell lymphoma without EBV infection and had an indolent clinical course with excellent prognosis. All patients in Group III developed acute myeloid leukemia (AML) during the course of CD. Two (67%) of these patients died of AML. Our study suggests that IBD-associated LMPD is very rare but can follow an aggressive clinical course., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation. In addition to reactivation of Epstein-Barr virus in immunocompromised patients, impaired tumor immunity is suggested to be a risk factor for PTLD. However, it remains unclear whether immune suppressive tumor-infiltrating lymphocytes (TILs) correlate with the occurrence or prognosis of PTLD. We analyzed TILs in 26 patients with PTLD to elucidate the clinicopathological significance of the expression of PD-1 and FoxP3, which are associated with exhausted T-cells and regulatory T-cells (Tregs), respectively. Numbers of PD-1 + TILs in the PTLD specimens were significantly higher in patients who developed PTLD early after transplantation (P = 0.0040), while numbers of FoxP3 + TILs were not (P = 0.184). There was no difference in overall response rate regardless of the expression of PD-1 or FoxP3. FoxP3 high patients tended to have a shorter time to progression compared with FoxP3 low patients, especially in the case of FoxP3 high patients with diffuse large B-cell lymphoma-subtype PTLD (P = 0.011), while PD-1 high patients did not. These results suggest that T-cell exhaustion may be mainly associated with PTLD development, while immune suppression by Tregs may be dominant in enhanced progression of PTLD following disease occurrence.

Epstein-Barr virus (EBV) normally infects B cells, but in some persons the virus infects T or NK cells. Infection of B cells can result in infectious mononucleosis, and the virus is associated with several B cell malignancies including Hodgkin lymphoma, Burkitt lymphoma, and diffuse large B cell lymphoma. Infection of T or NK cells with EBV is associated with extranodal NK/T cell lymphoma, aggressive NK-cell leukemia, systemic EBV-associated T-cell lymphoma, and chronic active EBV disease, which in some cases can include hydroa vacciniforme-like lymphoproliferative disease and severe mosquito bite allergy. While NK and T cell lymphoproliferative disease is more common in Asia and Latin America, increasing numbers of cases are being reported from the United States and Europe. This review focuses on classification, clinical findings, pathogenesis, and recent genetic advances in NK and T cell lymphoproliferative diseases associated with EBV.

Methotrexate-associated lymphoproliferative disorders are categorized as "other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8 + cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8 + cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus + tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8 + cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.

Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.

Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer 1,2 . Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification 1,2 . CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms 3 . Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF1 4-7 , while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

Chronic active Epstein-Barr virus infection (CAEBV) presents with mononucleosis-like symptoms such as chronic persistent or recurrent pyrexia, lymphadenopathy, and hepatosplenomegaly because of the reactivation of Epstein-Barr virus (EBV) as demonstrated by the recurrence of EBV-infected cells. The mechanism of CAEBV remains obscure, and CAEBV can lead to fatal conditions such as hemophagocytic syndrome and malignant lymphoma by clonal expansion of EBV-infected T- or NK-cells. Without hematopoietic stem cell transplantation, CAEBV has a poor prognosis. CAEBV is listed in the revised 2016 World Health Organization classification as a chronic active EBV infection of T- and NK-cell types, systemic form, among EBV-positive T- and NK-cell lymphoproliferative diseases of childhood. However, similar clinical conditions have been reported in adult patients. Therefore, we investigated the clinical features of adult patients with CAEBV-like features (adult-onset CAEBV) in a relatively small number of cases. Additionally, genetic alterations related to CAEBV development have also been reported. Along with these results, we reviewed the clinical characteristics of adult-onset CAEBV.

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever ( P =0.005), but greater frequency of skin lesions ( P <0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease ( P <0.001 and P =0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis ( P =0.0087, P =0.0236, and P =0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival ( P =0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis ( P <0.001 and P =0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed., (Copyright © 2018 Ferrata Storti Foundation.)

An adult woman developed polymorphic post-transplant lymphoproliferative disorder (PTLD) 58 months after unrelated cord blood transplantation. She was treated successfully with chemotherapy and radiation therapy but presented with lymphadenopathy and splenomegaly 74 months after transplantation. A lymph node biopsy confirmed the diagnosis of nodular sclerosis type Hodgkin lymphoma (classical Hodgkin lymphoma [CHL]-type PTLD). After salvage therapy and hematopoietic stem cell harvesting, she was subsequently treated with consolidative high-dose chemotherapy with melphalan followed by stem cell rescue, which resulted in durable remission. High-dose chemotherapy using stem cell rescue has potential as a therapeutic option for subsequent CHL-type PTLD.

We performed gene expression profiling in Epstein-Barr virus (EBV)-associated T/natural killer (NK)-cell lymphoproliferative disorder in children and young adults (TNKLPDC) in order to understand the molecular pathways deregulated in this disease and compared it with nasal-type NK/T-cell lymphoma (NKTL). The molecular and phenotypic signature of TNKLPDC is similar to NKTL, with overexpression of p53, survivin and EZH2. Down-regulation of EZH2 in TNKLPDC cell lines led to an increase in apoptosis and decrease in tumor viability, suggesting that EZH2 may be important for the survival of TNKLPDC cells and hence potentially a useful therapeutic target. Notably, our gene expression profiling revealed a distinctive enrichment of stem cell related genes in TNKLPDC compared to NKTL. This was validated by a significantly higher expression of aldehyde dehydrogenase 1 (ALDH1) in TNKLPDC cell lines compared to NKTL cell lines. The novel discovery of cancer stem cell properties in TNKLPDC has potential therapeutic implications in this group of disorders.

Background: EBV-associated T/NK-cell lymphoproliferative diseases (TNKLPD) is a rare spectrum of disease that occurs more commonly in Asia, and Central and South America. It commonly affects children and young adults and is an aggressive disease that is poorly understood with no known biologic markers that can predict prognosis. The systemic form of TNKLPD includes chronic active EBV infection of T/NK type, aggressive NK cell leukemia and systemic EBV + T-cell lymphoproliferative disease of childhood., Methods: In this study, we analyse the clinicopathologic and genetic features of 22 cases of systemic TNKLPD in non-immunocompromised patients, including chronic active EBV infection of T/NK cell type and systemic EBV + T-cell lymphoproliferative disease of childhood. We also performed gene expression profiling in a subset of cases to identify markers that may be of prognostic relevance and validated our results using immunohistochemistry., Results: The median age is 14.9 years and two of our 22 cases occurring in patients older than 30 years. Fifteen of 17 cases (88%) with adequate data were of T-cell origin. Eleven of 22 cases revealed polymorphic cellular infiltrate (P-group) while the rest showed monomorphic lymphoid infiltrate (M-group). We found a significant difference in survival between P-group vs M-group patients with median survival not yet reached in P-group, and 1 month in M-group (p = 0.0001), suggesting a role for morphology in predicting patient outcome. We also performed gene expression profiling in a subset of patients and compared the genes differentially expressed between P-group and M-group cases to identify markers of prognostic value. We identified cyclin E2 gene and protein to be differentially expressed between patients with good outcome (P-group, median expression 8%) and poor outcome (M-group, median expression 42%) (p = 0.0005). In addition, the upregulation of cyclin E2 protein in M-group cases correlated with a higher Ki67 proliferation rate (Pearson correlation r = 0.73, p = 0.0006) detected by immunohistochemistry. High cyclin E2 expression was also significantly associated with shorter survival (p = 0.0002)., Conclusion: Our data suggests the potential role of monomorphic morphology, high cyclin E2 and Ki67 expression as adverse prognostic factors for TNKLPD.

A 70-year-old man presented with papular skin lesions and was diagnosed with Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD). The patient showed infiltration of a large number of EBV-encoded RNA-positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV-infected γδ T cells and CD8(+) T cells in the blood and skin, as assessed by EBV-terminal repeat Southern blot, T-cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV-associated T/natural killer (NK)-LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection (CAEBV), and the latter group typically suffers from extranodal NK/T-cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients., (© 2014 Japanese Dermatological Association.)

We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.

Objectives: 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)., Methods: We evaluated the clinicopathological features, clinical characteristics, and treatment outcomes in 102 cases of RA-LPD. In addition, EBV infection and clonality of immunoglobulin heavy chain gene (IGH) were analyzed by in situ hybridization and polymerase chain reaction, respectively., Results: The 102 cases included patients with diffuse large B-cell lymphoma (DLBCL; n = 53), Hodgkin lymphoma (n = 9), polymorphic B-cell LPD (n = 20), reactive lymphadenitis (n = 11), peripheral T-cell lymphoma (PTCL; n = 4), composite lymphoma (n = 2), and follicular lymphoma (n = 3). EBV was detected in 60% (56/93) of patients. Spontaneous regression occurred in 59% (28/47) of patients in whom MTX was withdrawn. Regression was associated with EBV positivity (P = 0.007) and non-DLBCL (P = 0.006), but not with MTX amount and other clinical features. Monoclonal bands of IGH were observed in 31 of 74 cases. In patients with DLBCL, poor disease-free survival (P = 0.05) was associated with clonality of IGH. In all patients, factors predictive of shorter survival were age (>70 yr) and histological type of DLBCL., Conclusions: Histology, EBV positivity, and monoclonality of IGH are useful for predicting clinical outcomes in patients with RA-LPD., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A negative regulator of the nuclear factor (NF)-κB pathway, A20 (TNFAIP3), is inactivated in several types of lymphomas; particularly in diffuse large B-cell lymphoma (DLBCL), classical Hodgkin's lymphoma, and extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue. These findings suggest that the NF-κB activation is related to A20 inactivation. Recently, A20 inactivation has also been observed in Epstein-Barr virus (EBV)-related lymphomas; however, this occurrence has not been well investigated. Moreover, NF-κB is a key molecule in activated B-cell-like (ABC)-type DLBCL; EBV-associated DLBCL is of the ABC type. Therefore, we focused on A20 deletions in EBV-associated lymphoproliferative disorders/lymphomas. Using fluorescent in situ hybridization analysis, A20 deletions were identified in 4 of 13 samples from patients with pyothorax-associated lymphoma (PAL) (31%), 3 of 20 samples from nasal-type NK/T cell lymphomas (NKTLs) (15%), 1 of 8 samples of EBV-positive DLBCL of the elderly (DLBCL-e) (13%), but not in any of the 11 samples from individuals with methotrexate-related lymphoproliferative disorder (MTX-LPD) (0%). Among the samples with A20 deletions, EBV latent membrane protein 1 (LMP-1) expression was detected in all 4 of the PAL samples with A20 deletions and in the DLBCL-e sample with an A20 deletion, but not in any of the 3 NKTL samples. This finding indicated that A20 deletions were not directly related to the EBV latency pattern of lymphomas, although such deletions might be related to the diagnostic category. Immunohistologically, the A20 protein was absent in 2 (15%) of the 13 PAL samples, 1 (9%) of 11 MTX-LPD samples, and in none of the 20 NKTL (0%) or 8 DLBCL-e samples. In conclusion, A20 deletion and/or dysfunctional expression are frequently associated with PALs, and A20 abnormalities may be related to the pathogenesis of PAL.

Purpose: To investigate the frequency of infraorbital nerve enlargement (IONE) in orbital lymphoproliferative disorders, and to show that IONE can contribute to the clinical diagnosis of IgG4-related orbital diseases (IgG4-ROD)., Subjects and Methods: 71 cases in which orbital lymphoproliferative disorders were diagnosed at Okayama Medical Center and Mitoyo General Hospital from April, 2004 to March, 2011 were investigated. The male-to-female ratio was 39:32, and the age range 27-87 years old (average age 64.1 years). Whenever the coronal section of the infraorbital nerve was larger than that of the optic nerve on MRI, it was defined as IONE., Results: The breakdown of the 71 cases was: 45 cases of non-Hodgkin lymphoma, 16 cases of IgG4-ROD, 5 cases of reactive lymphoid hyperplasia, and 5 cases of idiopathic orbital inflammation. Of these, a total of 9 cases had IONE. The incidence of IONE was compared between the IgG4-ROD patient group and the non-IgG4-ROD patient group and was significantly higher in the IgG4-ROD patient group (p < 0.0001)., Conclusion: If IONE is observed in a case of orbital lymphoproliferative disorders on MRI, then it is highly possible that such a case is IgG4-ROD.

We report immunoglobulin (Ig)G4-positive multi-organ lymphoproliferative syndrome (IgG4(+) -MOLPS) with antiphospholipid antibody syndrome (APS) in a 56-year-old Japanese man presenting with purpuric patches on his legs. Skin biopsy revealed leukocytoclastic vasculitis. Laboratory tests demonstrated high levels of serum IgG and IgG4, hypocomplementemia and anticardiolipin antibody. Echography of the lower limbs and pulmonary scintigraphy showed a thrombus in the left soleal vein and multiple emboli in the basal part of both inferior pulmonary arteries. Computed tomography revealed systemic lymphadenopathy. Histologically, there was reactive paracortical hyperplasia with proliferation of histiocytes and infiltration of IgG4-positive plasma cells. We made a diagnosis of IgG4(+) -MOLPS with APS. To our knowledge, this complication has not been reported previously., (© 2012 Japanese Dermatological Association.)

This report describes a case of an immunocompetent 77-year-old male with Epstein-Barr virus (EBV)-positive lymphoproliferative disorder associated with calcified chronic subdural hematoma (CSH). On the day prior to consultation in our outpatient clinic, the patient fell from his bed, striking his frontal head on the floor. Magnetic resonance imaging showed ill-defined lesions in the right frontal-temporal subdural regions. At surgery, a hard and thickened outer membrane of a CSH and muddy organized subdural hematoma were observed. However, macroscopic neoplastic lesions were not apparent. Histologically, there were atypical lymphoid cells scattered or conglomerated in some areas of the thick outer membrane of the CSH. They were composed of occasional large atypical lymphoid cells. The lesions were accompanied by necrosis. Atypical lymphoid cells were immunopositive for B-cell markers but not for T-cell markers. EBNA2 was seen in the nuclei of tumor cells. Atypical lymphoid cells showed positive signals for EBV-encoded small RNAs (EBERs) on in situ hybridization. These findings were consistent with EBV-positive lymphoproliferative disorder associated with CSH. These results also suggested that EBV and the inflammatory reaction found in the CSH could be the etiological factors in the pathogenesis of lymphoproliferative disorder., (© 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.)

EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) is defined as a systemic illness characterized by clonal proliferation of EBV-infected T or NK cells. We prospectively enrolled 108 nonimmunocompromised patients with this disease (50 men and 58 women; median onset age, 8 years; age range, 1-50 years) evidenced by expansion of EBV(+) T/NK cells in the peripheral blood; these were of the T-cell type in 64 cases and of the NK-cell type in 44, and were clinically categorized into 4 groups: 80 cases of chronic active EBV disease, 15 of EBV-associated hemophagocytic lymphohistiocytosis, 9 of severe mosquito bite allergy, and 4 of hydroa vacciniforme. These clinical profiles were closely linked with the EBV(+) cell immunophenotypes. In a median follow-up period of 46 months, 47 patients (44%) died of severe organ complications. During the follow-up, 13 patients developed overt lymphoma or leukemia characterized by extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Fifty-nine received hematopoietic stem cell transplantation, 66% of whom survived. Age at onset of disease (≥ 8 years) and liver dysfunction were risk factors for mortality, whereas patients who received transplantation had a better prognosis. These data depict clinical characteristics of systemic EBV(+) T/NK-LPD and provide insight into the diagnostic and therapeutic approaches for distinct disease.

Aims: Extranodal natural killer (NK)/T-cell lymphoma (NKTL), comprising nasal NKTL and extranasal NKTL (ENKTL), is associated with Epstein-Barr virus (EBV). A bimodal age distribution was noted in NKTL patients. We examined the clinicopathological differences between two age groups of ENKTL patients (n = 23) and compared the findings with those of aggressive NK cell leukaemia (ANKL; n = 10) and monoclonal chronic active EBV infection-associated T/NK-cell lymphoproliferative disorders [chronic active EBV infection/TNK-lymphoproliferative disorders (CAEBV/TNK-LPD)] of NK-cell type (n = 45)., Methods and Results: Distinct differences existed between elderly (> 50 years; n = 13) and younger (≤ 50 years; n = 10) ENKTL patients; the latter showed a higher disease stage (P = 0.0286), worse performance status (P = 0.0244), more frequent B symptoms (P = 0.0286) and more frequent liver, spleen and bone marrow involvement (P = 0.0222, 0.0005 and 0.0259, respectively). Few clinicopathological differences existed between younger ENKTL and ANKL patients. Patients with monoclonal CAEBV/TNK-LPD of NK-cell type (n = 45) showed features similar to those in younger ENKTL/ANKL patients, except a more juvenile onset of CAEBV-related symptoms and better prognosis. However, the onset age of overt leukaemia/lymphoma in CAEBV/TNK-LPD patients and overall survival thereafter were similar to those in younger ENKTL/ANKL patients., Conclusions: ENKTL (≤ 50 years) is distinct from that in elderly patients and may encompass ANKL and overlap in the clinicopathological profile with NK-cell type CAEBV/TNK-LPD., (2011 Blackwell Publishing Limited.)

Background: In Japan, chronic active Epstein-Barr virus infection (CAEBV) may manifest with infection of T-cells or NK-cells, clonal lymphoid proliferations, and overt lymphoid malignancy. These EBV-positive lymphoproliferative disorders (EBV(+)LPD) of childhood are related to, but distinct from the infectious mononucleosis-like CAEBV seen in Western populations. The clonal nature of viral infection within lymphoid subsets of patients with EBV(+)LPD of childhood is not well described., Objectives: Viral distribution and clonotype were assessed within T-cell subsets, NK-cells, and CD34(+)stem cells following high purity cell sorting., Study Design: Six Japanese patients with EBV(+)LPD of childhood (3 T-cell LPD and 3 NK-cell LPD) were recruited. Prior to immunochemotherapy, viral loads and clonal analyses of T-cell subsets, NK-cells, and CD34(+)stem cells were studied by high-accuracy cell sorting (>99.5%), Southern blotting and real-time polymerase chain reaction., Results: Patient 1 had a monoclonal proliferation of EBV-infected γδT-cells and carried a lower copy number of EBV in αβT-cells. Patients 2 and 3 had clonal expansions of EBV-infected CD4(+)T-cells, and lower EBV load in NK-cells. Patients 4, 5 and 6 had EBV(+)NK-cell expansions with higher EBV load than T-cells. EBV-terminal repeats were determined as clonal bands in the minor targeted populations of 5 patients. The size of terminal repeats indicated the same clonotype in minor subsets as in the major subsets of four patients. EBV was not, however, detected in the bone marrow-derived CD34(+)stem cells of patients., Conclusions: A single EBV clonotype may infect multiple NK-cell and T-cell subsets of patients with EBV(+)LPD of childhood. CD34(+)stem cells are spared, suggesting infection of more differentiated elements., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Chronic active Epstein-Barr virus (EBV) infection, which is considered to be a childhood disease, often develops into natural killer (NK) or T-cell lymphoma after recurrent infectious mononucleosis (IM)-like symptoms. We describe a 56-year-old woman who developed NK-cell lymphoma after 9 months of recurrent IM-like symptoms. The patient had an unusual anti-EBV antibody profile. Increased levels of EBV genome were detected in the liver and peripheral blood. Several chemotherapy regimens were ineffective, and the patient died of progression of lymphoma. Certain subtypes of NK-cell lymphoma showing a long-lasting prodrome related to chronic EBV infection may exist.

EBV-associated T/natural killer (NK)-cell lymphoproliferative disorder (EBV-T/NK LPD) of children and young adults is generally referred to with the blanket nosological term of severe chronic active EBV infection (CAEBV). This disease is rare, associated with high morbidity and mortality, and appears to be more prevalent in East Asian countries. But because there is no grading or categorization system for CAEBV, pathologists and clinicians often disagree regarding diagnosis and therapy. EBV-T/NK LPD includes polyclonal, oligoclonal, and monoclonal proliferation of cytotoxic T and/or NK cells. Moreover, a unique disease previously described as infantile fulminant EBV-associated T-LPD has been identified and overlaps with EBV-T/NK LPD. In the present review a clinicopathological categorization of EBV-T/NK LPD is proposed, based on pathological evaluation and molecular data, as follows: (i) category A1, polymorphic LPD without clonal proliferation of EBV-infected cells; (ii) category A2, polymorphic LPD with clonality; (iii) category A3, monomorphic LPD (T-cell or NK cell lymphoma/leukemia) with clonality; and (iv) category B, monomorphic LPD (T-cell lymphoma) with clonality and fulminant course. Categories A1, A2, and A3 possibly constitute a continuous spectrum and together are equivalent to CAEBV. Category B is the exact equivalent of infantile fulminant EBV-associated T-LPD. It is expected that this categorization system will provide a guide for the better understanding of this disorder. This proposal was approved at the third meeting of the Asian Hematopathology Association (Nagoya, 2006).

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.

X-linked lymphoproliferative syndrome (XLP) is a rare, often fatal, primary immunodeficiency disease characterized by an abnormal response to Epstein-Barr virus (EBV) infection. The gene responsible for XLP has been identified as SH2D1A/DSHP/SLAM-associated protein (SAP). The major clinical manifestations include fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia. Affected males uncommonly present with lymphocytic vasculitis in addition to aplastic anemia. In this study, we describe a Japanese XLP patient who presented with hypogammaglobulinemia following acute EBV-induced infectious mononucleosis in the infancy and later had systemic lymphocytic vasculitis and hemophagocytic lymphohistiocytosis in the adulthood, which resolved by steroid pulse therapy. The patient's SAP gene was found to harbor a missense mutation (His8Asp), presumably resulting in defective expression of SAP in T cells. Biopsy specimens of lung and skin disclosed that CD8+ T cells predominantly infiltrated vascular vessels. However, immunohistochemical examination showed that EBV-infected cells were not identifiable in the vessels. We propose that T-cell-mediated immune dysregulation in XLP can cause vasculitis by EBV infection-unrelated mechanism., (Copyright 2005 Wiley-Liss, Inc.)

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disorders (LPD) of children and young adults are sometimes termed as severe chronic active EBV infection (CAEBV), and are associated with an aggressive clinical course. However, these clinicopathological states and the role of EBV have not been clarified. A retrospective study was performed on 43 children and adult patients, who manifested EBV-associated T/NK-cell lymphoproliferative disorders (EBV-T/NK-LPD) and most of whom had experienced general illness with CAEBV for several months or years. Clinicopathologically, 43 patients were classified into four groups: group A (smoldering state) (n=7), morphological non-neoplastic LPD with chronic clinical course (several years); group B (chronic state) (n=10), non-neoplastic LPD with clonal EBV-infected cells and a chronic course; group C (leukemia/lymphoma state) (n=22), neoplastic LPD with a subacute course (years to months); group D (fulminant state) (n=4), neoplastic LPD with a fulminant course (weeks to days). The 43 patients comprised 21 males and 22 females. The median age of group A was 14 years, group B 12 years, group C 17 years, and group D 1 year. Four of 7 patients in group A, 3 of 10 in group B, 12 of 22 in group C, and all 4 in group D have died. Causes of death included hemophagocytic syndrome and/or tumor death. Genotypically and phenotypically, group C was composed of peripheral T-cell lymphoma (PTCL), and NK-cell leukemia/lymphoma (NKLL), and group D comprised cases of PTCL. Groups A and B exhibited increased NK- or T-cells (CD8>CD4), and rare B-cells. Serologic titers of EBV were only modestly elevated or not elevated in almost all cases. EBV early RNA-1 (EBER-1)-expressing EBV-infected cells were frequently encountered in each group, but the number of infected cells varied between the cases. The EBV genotype did not differ between the groups. Our findings support an important pathogenic role for EBV-infected T/NK-cell infection, rather than the EBV state, in CAEBV and consequent EBV-associated NK/T-neoplasia.

T cell immunity plays an important role in the clinicopathology of Epstein-Barr virus (EBV)-associated diseases. Acute EBV-induced infectious mononucleosis (IM) is a common self-limiting disease, however, other EBV-associated diseases, including chronic active EBV infection (CAEBV), NK cell lymphoma (NKL), and Hodgkin's lymphoma (HL), exhibit distinct clinical features. Chemokines are members of a family of small-secreted proteins. The relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity. Some chemokines, chemokine R and cytokines closely associate with the T cell subtypes, Th1 and Th2 T cells and cytotoxic cells. To clarify the role of T cell immunity in EBV-associated diseases, we conducted gene expression profiling, using chemokine, chemokine R and cytokine DNA chips. Compared to EBV negative non-specific lymphadenitis, CAEBV and NKL exhibited diffuse down- and up-regulation, respectively, of these gene profiles. IM had a predominantly Th1-type profile, whereas HL had a mixed Th1/Th2-type profile. Reduction of the Th1-type cytokine interferon gamma (IFN-gamma) in CAEBV was confirmed by Reverse transcriptase-polymerase chain reaction, whereas IFN-gamma expression was markedly enhanced in NKL, and moderately enhanced in IM. Compared to IM, CAEBV showed slight elevation of "regulated upon activation, normal T expressed and secreted" (RANTES), but almost all other genes assayed were down-regulated. NKL exhibited elevated expression of numerous genes, particularly IFN-gamma-inducible-10 (IP-10) and monokine induced by IFN-gamma (MIG). HL showed variable elevated and reduced expression of various genes, with increased expression of IL-13 receptor and MIG. Our study demonstrated the enormous potential of gene expression profiling for clarifying the pathogenesis of EBV-associated diseases.

It is reported that overexpression of hnRNP A2 and B1 proteins is useful for detecting early cancers, and that B1, a splicing minor isoform of A2, is more specific than A2. The B1 expression is still undetermined in human lymphoid tissues. We quantitatively studied the B1 expression in 85 lymph node specimens, comprising reactive lymphoid hyperplasia (RLH; n=8), B-cell lymphoma (n=23), T-cell lymphoma (n=22), and metastatic carcinoma (n=32). Immunostaining and immunoblotting analyses with an anti-B1 monoclonal antibody, 2B2 were performed, and the two sets of results correlated with each other (p<0.05). In RLH specimens, B1 expression rate was significantly higher in follicular centers (FC; 44%) than in mantle zone (MZ; 15%) and paracortex (16%) (p<0.01). B1 expression was statistically higher in B-cell lymphoma than in T-cell lymphoma (p<0.01). In B-cell lymphomas, B1 expression rates were 51% in diffuse large B-cell lymphoma (DLBL; n=5) and 45% in follicular lymphoma (FL; n=16), and they were almost the same as that of the FC. Especially in DLBLs, CD10+ FC-origin lymphomas expressed greater amount of B1 than CD10- non-FC-origin lymphomas. B1 expression rate was low in mantle cell lymphoma (MCL; n=2) and similar to that of MZ in RLH. These results suggest that B1 expression is associated with differentiation in lymphoid tissue rather than transformation. B1 expression increases during the process of B-cell differentiation in the FC, and that high B1 expression is maintained in B-cell lymphomagenesis, especially in cells of FC-origin DLBL.

A 24-year-old Japanese male was admitted to our hospital because of lymphadenopathy in his left neck. He had a nine-year history of chronic renal failure, and had received an ABO-mismatched renal allograft and splenectomy in August 2000 after one year of hemodialysis treatment. After renal transplantation, he was treated with FK506, methylprednisolone (mPSL), and mycophenolate mofetil (MMF) as an immunosuppressants for his graft maintenance. On admission, April 2001, he underwent lymphadenectomy, and the immunohistochemical studies revealed that the tumor cells expressed EBV-LMP and EBNA-2 antigens with the histology of diffuse large B-cell lymphoma. Our diagnosis was an Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), and we reduced the dose of immunosuppressive agents and treated the patient with rituximab. In this case, there may have been two principal risk factors associated with PTLD: first, the patient was treated with higher levels of immunosuppressive agents because of the ABO-mismatched transplantation, and second, he was an EBV-seronegative recipient at the time of pretransplantation.

Post-transplant lymphoproliferative disorders (PTLD) of T cell type are a rare complication of solid organ and allogeneic hematopoietic cell transplantation (HCT), and usually are not associated with Epstein-Barr virus (EBV) infection. EBV-associated T cell PTLD has not been reported to occur after autologous HCT. We report an unusual case of T cell lymphoproliferation after autologous blood stem cell transplantation (ABSCT). A patient with relapsed Hodgkin's disease developed abdominal lymphadenopathy followed by atypical CD8+ lymphocytosis in the peripheral blood 30 months following ABSCT. DNA studies of the atypical lymphocytes demonstrated rearrangements of the T cell receptor beta gene and a clonal proliferation of EBV.

Recently, we showed that 5 cases of hypersensitivity to mosquito bites (HMB) concealed the clonal lymphoproliferation of Epstein-Barr viral (EBV) DNA-positive natural killer (NK) cells. Although the symptoms of HMB have been supposed to derive from Arthus phenomenon, it has become apparent that this unique disorder has the potential to develop into so-called malignant histiocytosis (MH) or related disorders. Accordingly, the criteria for MH have been changed, and a newer diagnostic name, hemophagocytic syndrome, has been described as being associated with viral infection or leukemia/lymphoma. We previously reported that biopsy specimens taken from skin lesions demonstrated infiltration of lymphocytes bearing the phenotype of NK cells. In this study, we found that skin lesions exhibited infiltration of atypical lymphocytes around the small vessels, resembling angiocentric lymphoma, and that these infiltrating cells were positive for EBER-1 by in situ hybridization. These findings support the concept that HMB is the most important manifestation of a certain type of lymphoproliferative disease that presents with an intense local skin reaction and high fever following mosquito bites, and whose essence is the lymphoproliferation of EBV DNA-positive NK cells.

Primary pulmonary lymphoproliferative disorders (PLDs) are histologically divided into a neoplastic state of high and low grade malignant lymphoma (ML), and a reactive state of follicular bronchitis/bronchiolitis (FB) and lymphoid interstitial pneumonia (LIP). We reviewed 19 cases with PLDs, including 4 cases each of high and low grade B cell ML, 6 FB cases, and 5 cases of LIP. To clarify the clonality of the proliferating cells, we performed an immunohistochemical examination (IHC), in situ hybridization (ISH) for the immunoglobulin light chain and a polymerase chain reaction (PCR) analysis of the immunoglobulin heavy chain gene using DNA obtained from paraffin sections. In addition, a Southern blot analysis was also performed in 6 cases using fresh materials. In IHC, all ML were positive for L26 (CD20), while the monoclonality of the kappa light chain was observed in only one high grade case. However, using ISH we could detect the clonality in three of four high grade ML cases and in one of four low grade ML cases. In FB and LIP, no clonality of immunoglobulin by ISH was observed. In a PCR analysis for the immunoglobulin heavy chain gene, we could detect one or two prominent bands in all 8 cases of high and low grade ML. On the other hand, in all cases of FB and LIP, we could only detect either an oligoclonal or polyclonal population. In summary, the presence of monoclonality of ISH and/or PCR for the immunoglobulin heavy chain gene were limited in the neoplastic state, but not in the reactive state.

To assess the abnormal T-cell expansion in chronic active Epstein-Barr virus infection (CAEBV), T-cell antigen receptor (TCR) repertoire was analyzed in four patients with the disease. All fulfilled the diagnostic criteria of CAEBV, presenting with fever, hepatosplenomegaly, cytopenia, abnormal high titers of anti EBV-antibodies, and positive EBV genome of unknown cause. Southern blotting probed with EBV-terminal repeats and TCR Cbeta gene indicated clonal expansion of the infected cells in 3 and 2 patients, respectively. The number of CD4+ HLA-DR+ cells appreciably increased in patients 1 (59%) and 2 (24%), who had a coronary aneurysm and central nervous system involvement, respectively. TCR gene expression examined by the inverse polymerase chain reaction methods revealed that Vbeta gene usages were preferential in all patients (Vbeta7 and Vbeta12: patient 1, Vbeta4: patient 2, Vbeta13: patients 3 and 4), compared with those in healthy controls. Valpha18 gene expression was remarkably high in patients 1 and 2. Moreover, Jbeta gene expression was skewing in the reigning Vbeta clones in all patients. Vbeta4-Jbeta1.5 and Vbeta13-Jbeta1.5 genes were clonally expressed in patients 2 and 4, respectively. These results suggest that CAEBV is associated with the restricted diversity of T-cells, which may stem from the sustained expansion of oligoclonal T-cells possibly driven by conventional viral antigens, but not, superantigens. Although the study is limited by the small number of patients, the unbalanced T-cell repertoire might contribute to the evolution of T-lymphoproliferative disease, otherwise, imply the innate defective immunity to EBV in CAEBV patients.

Purpose: Central nervous system (CNS)-T cell lymphoproliferative disorder (T-LPD) developing during the course of chronic active Epstein-Barr virus (CAEBV) infection is reported., Patients and Methods: CAEBV was diagnosed in a 14-month-old boy with fever, cytopenia, hepatosplenomegaly, and abnormal high titers of anti-Epstein-Barr virus (EBV) antibodies. At 8 years of age, he had a splenectomy because of progressive disease., Results: After 27 months of clinical remission, muscle weakness and paresthesia developed. Magnetic resonance imaging of his brain showed spotty T2 prolongation in left parietal, bilateral frontal, and temporal white matter with meningeal enhancement. Brain biopsy revealed the cerebral infiltration of CD3+, CD4+, CD8-, CD45RO+, CD56-, and EBV-encoded RNA 1+ cells., Conclusions: The CNS involvement of EBV-associated T-LPD is a rare but serious complication in CAEBV without known underlying immunodeficiency.

We evaluated the serum level of soluble Fas ligand (sFasL) in patients with natural killer lymphocyte proliferative disorders (NK- LPD). The serum sFasL level was elevated in neoplastic groups of aggressive NK leukaemia, indolent NK leukaemia and NK lymphoma, all of which contained clonal EBV-DNA. In NK leukaemia the serum sFasL level was significantly higher than that found in others. However, it was not elevated in the patients with reactive NK-LPD and in one patient with NK leukaemia in remission. These findings indicate that the serum sFasL level is a useful indicator in evaluating disease activity.

Chronic active Epstein-Barr virus (CAEBV) infection has been previously reported to be sometimes associated with an aggressive clinical course. However, the role of EBV in the CAEBV is not well clarified. A retrospective study was performed on nine adult and five child patients (eight males and six females). Histologically, at first admission, the presence of neoplastic lesions could not be confirmed. The lymph nodes in half of all cases revealed paracortical hyperplasia with transformed lymphocytes (hyperplastic type). Half of the cases showed non-suppurative necrosis and an increased number of histiocytes with phagocytosis (histiocytic type). Activated histiocytes with lymphokine positivity were frequently detected in the histiocytic type. In the phenotypical study, 10 of the examined 11 cases showed increased numbers of natural killer (NK) cells and/or CD8-positive T lymphocytes. In situ hybridization (ISH) showed EBV-infected lymphoid cells, but the number of EBV-infected cells varied. Double-labeling immunochemistry/ISH demonstrated EBV-infected T cells, including NK cells, but not B cells. In addition, three cases showed a monoclonal dissemination of EBV terminal repetitive sequence (TR), and two cases showed oligoclonal dissemination. From those findings, monoclonal, oligoclonal and polyclonal populations of EBV-infected T or NK cells were considered to be present in CAEBV states. During the clinical course, 12 of the 14 cases died within 5 years. Six cases died from EBV-associated hematopoietic tumors (histiocytic tumor, T cell lymphoma, B cell lymphoma, plasmacytoma, and NK cell leukemia); one from non-EBV-associated acute myelogenous leukemia, and five due to hemophagocytic syndrome. The examined EBV-associated hematopoietic tumors showed monoclonal EBV terminal repetitive sequences. There is a possibility that the monoclonal dissemination of EBV-infected cells develops from oligoclonal or polyclonal EBV-infected cells. And active histiocytes with lymphokine positivity were frequently detected in the cases with histologically histiocytic type. These findings seem to be related with the causes of death due to hemophagocytic syndrome.

In order to clarify the relationship between Epstein-Barr (EB) virus and hypersensitivity to mosquito bites (HMB), and to search for the mechanism which induces EB virus-associated lymphoproliferative diseases, we investigated patients with HMB, using hematological, immunological and virological techniques. Among 5 cases of HMB, CD56+ cells had proliferated and CD3+ cells were diminished in 4 cases. Although anti-EB virus antibody titers were not consistent with chronic active EB virus infection, EB viral DNA was detected in the peripheral blood mononuclear cells in all 5 cases. Moreover, EB viral DNA-positive cells had proliferated monoclonally in 4 cases, and biclonally in 1 case. It was proved that most of the EB viral DNA existed in natural killer (NK) cells through polymerase chain reaction analysis. These findings suggest that the basis of HMB may be clonal lymphoproliferation of EB viral DNA-positive NK cells and this hematological abnormality may induce the characteristic symptoms of HMB. In some cases, the proliferating NK cells can metamorphose into leukemic cells, and hemophagocytic syndrome, which has been assumed to be a complication of HMB, may then occur.

Using the polymerase chain reaction (PCR) to examine the occurrence of bcl-2/JH joining produced by t(14;18) chromosomal translocation, amplified DNA was detected in 2 of 18 lymph nodes showing reactive lymphadenopathy. The PCR was repeated in these two lymph nodes using the same DNA samples, but no amplification was detected at the second attempt. Thus the amplified DNA was considered to be derived from one copy of joined bcl-2/JH in one cell, or from a few copies in a few clonal cells with the same joined bcl-2/JH. These results suggest that false joining of bcl-2/JH at the t(14;18) junction may occur in reactive lymph nodes.

We analyzed the rearrangement of T-cell receptor (TcR) delta chain gene in 88 cases of lymphoproliferative disorders; 31 acute lymphoblastic leukemias/lymphoblastic lymphomas (ALL/LBL); 27 adult T-cell leukemias/lymphomas, 9 angioimmunoblastic lymphoadenopathies (AILD); 10 T-cell lymphomas (non-Hodgkin's lymphoma); and 11 Hodgkin's disease. All of 9 T-ALL/LBL cases, of which 4 cases have neither beta nor gamma gene rearrangement, had a new rearranged band of TcR delta locus. Ten of 16 B-lineage ALL/LBL had rearranged band(s) or deletion of TcR delta locus. The rearranged bands were recognized in 2 cases of AILD and 1 case of T-cell lymphoma. All cases of adult T-cell leukemias/lymphomas, 4 of AILD, 4 of T-cell lymphoma, and 8 of Hodgkin's disease had deleted TcR delta locus. Heterogeneous findings of TcR delta locus analysis were observed in AILD, T-cell lymphoma, and Hodgkin's disease. In 16 cases with TcR delta rearrangement, the J delta 1 region was frequently used and the J delta 2 region was rearranged in one AILD. It is suspected that J delta 3 was used in one T-ALL/LBL. There was no correlation between the phenotypic pattern of CD3, CD4, CD8 in T-cell disorders and the rearrangement of the TcR delta gene. These findings suggest that the newly identified TcR delta chain gene rearranges at a very early stage of T-cell ontogeny; prior to the other TcR genes and perhaps at almost the same stage with CD7 expression. The TcR delta gene is useful in assessing clonality for the most immature T-cell neoplasms not showing rearrangement of the other TcR genes. This gene is not lineage specific; however, when used in conjunction with immunoglobulin heavy chain gene, it may be a useful tool to distinguish lymphoid lineage of ALL/LBL.

Background Little is known about the mechanisms involved in skin-specific homing in CD30+ cutaneous lymphoproliferative disorders (CLPD). Chemokine/chemokine receptor interactions have been implicated in the homing of lymphoma cells to various tissue sites. Objectives To investigate tissue samples from patients with CD30+ CLPD for the expression of the chemokine receptors CXCR3, CCR4 and CCR3 and their ligands MIG, TARC and RANTES. Methods Tissue samples from patients with primary cutaneous anaplastic large cell lymphoma (PCALCL, n = 12) and lymphomatoid papulosis (LyP, n = 13) were studied by immunohistochemistry on paraffin-embedded sections. Immunohistochemical analysis was also performed for CD20 (for B cells), CD45RO and CD3 (for T cells), CD30 and ALK-1. A portion of each skin specimen was stored at − 80 °C and later examined using monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD15, CD19, CD20 and CD30. Results CD30+ atypical lymphoid cells were frequently seen in PCALCL, and to a variable degree in LyP. In both disorders there were scattered CD3+ and CD45RO+ atypical lymphoid cells, but CD2, CD5, CD15, CD19, CD20 and ALK-1 showed negative reactivity. In addition, CD4+, but not CD8+, atypical lymphoid cells were occasionally seen in both disorders. CCR3 was expressed by atypical lymphoid cells in 10 of 12 (83%) cases of PCALCL, but in only five of 13 (38%) cases of LyP. CXCR3 was expressed in 11 of 13 (85%) cases of LyP, but in only one of 12 (8%) cases of PCALCL. CCR4 was expressed in 11 of 12 (92%) cases of PCALCL, but in only two of 13 (15%) cases of LyP. RANTES was strongly expressed by lymphoma cells in PCALCL (11 of 12: 92%), but was weak or sporadic in LyP (seven of 13: 54%). TARC showed weak or sporadic reactivity in both LyP and PCALCL, and MIG did not show a distinctive expression pattern in either disorder. Conclusions We speculate that CCR3 is associated with the autocrine function in PCALCL, as evidenced by CCR3 coexpression with its ligand RANTES. We also found that LyP cells expressed CXCR3, which might support their migration towards the CXCR3 ligand MIG, which is expressed in stromal cells of the skin. [ABSTRACT FROM AUTHOR]

Aims: Lymphomatous polyposis (LP) is considered to represent mantle cell lymphoma (MCL) of the gastrointestinal (GI) tract. However, a few reports have suggested that some are follicular lymphoma (FL) or mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we analysed 35 patients and clarified the clinicopathological features of LP. Methods and results: Paraffin-embedded tissue samples were stained immunohistochemically and analysed by tissue-fluorescence in situ hybridization (T-FISH) for IGH/CCND1 (cyclin D1) and IGH/BCL2. The average age of the patients was 58.3 years. Over half of the cases showed gastric, duodenal, small intestinal, ileocaecal and sigmoid colonic lesions (15, 19, 15, 16 and 16 cases, respectively). Phenotypically, cases were classified into three types of MCL (cyclin D1+ CD5+ CD10–) ( n = 12), FL (cyclin D1– CD5– CD10+) ( n = 14) and MALT (cyclin D1– CD5– CD10–) ( n = 9). T-FISH identified 11 of the 11 examined cases with MCLs to have IGH/CCND1, while seven of 10 cases with FL had IGH/BCL2, and none of the MALT cases were positive for IGH/CCND1 or IGH/BCL2. At the study endpoint, five of 12 patients with MCL were dead, two of 14 with FL and one of nine with MALT were dead of other disease. Event-free survival analysis showed significantly poorest outcome in MCL, followed by FL, while MALT was associated with a favourable outcome ( P = 0.0040). Conclusions: Our study emphasizes the importance of differentiating MCL, FL and MALT of LP in evaluating prognosis and hence the most suitable therapeutic regimen. [ABSTRACT FROM AUTHOR]

Follicular lymphomas (FL) are morphologically classified into grades 1, 2, 3a and 3b by the World Health Organization. Bcl2, Bcl6 and CD10 are phenotypic markers of FL while the Bcl2 t(14;18) and Bcl6 t(3q27) gene translocations are common genetic changes. However, to date, there has been no integrated analysis based on phenotype, grade and genotype from large numbers of FL cases. We graded 261 cases of FL and determined their phenotypes and gene alterations. According to the antigen markers and gene alterations of 147 cases, we classified FL into typical and the others types. The typical group, which includes 69% cases of FL, is characterized by low histological grade (grade 1, 2), coexpression of BCL2 and CD10 and Bcl2 gene translocation. The rest comprises a small part of low-grade FL without Bcl2 gene translocation and high-grade (grade 3a, 3b) FL. These FLs include some heterogeneous disease entities. They are characterized by high histological grade (87%), no definite expression of BCL2 or CD10 and several kinds of gene aberrances including Bcl2 translocation, Bcl6 translocation, Bcl2 amplification or other unknown gene abnormality. Our findings indicate that typical FL presents a homogeneous disease entity whereas the rest comprises heterogeneous diseases entities. [ABSTRACT FROM AUTHOR]

A 7-year-old boy with Diamond-Blackfan anemia (DBA) developed lymphoproliferative disease (LPD) after a cord blood transplant (CBT). 3.1 × 107/kg mononuclear cells from an HLA one-locus mismatched CB were transplanted after conditioning with total body irradiation (8 Gy), cyclophosphamide (200 mg/kg) and antithymocyte globulin (10 mg/kg). Complete engraftment occurred on day 33 post transplant. Despite the resolution of grade II graft-versus-host disease (GVHD), he died of lymphoma on day 130 post transplant. The tumor was of donor origin, indicating clonal proliferation of Epstein–Barr virus (EBV)-infected B cells. This is the first report of EBV-LPD after CBT. Post-transplant LPD can be a serious EBV-associated complication of CB grafts. Bone Marrow Transplantation (2000) 25, 209–212. [ABSTRACT FROM AUTHOR]