EBV status has prognostic implication among young patients with angioimmunoblastic T-cell lymphoma.

Epstein-Barr virus (EBV)-positive B cells have been detected in 66%-86% of patients with angioimmunoblastic T-cell lymphoma (AITL). However, it remains controversial whether EBV status has an impact on the survival of patients with AITL. In this study, we aimed to reevaluate the impact of EBV on the clinicopathological characteristics of AITL. In particular, we focused on the impact of EBV in younger patients with AITL. In total, 270 cases of AITL were studied. Epstein-Barr virus-positive B cells were detected in 191 (71%) cases (EBER+ group). Among the patients who received anthracycline-based therapy, the EBER status did not affect the overall survival (OS) or progression-free survival (PFS). In the younger group of AITL (≤60 years), PFS was significantly worse in the EBER- group compared to the EBER+ group (P = .0013). Furthermore, the multivariate analysis identified EBER-negative status, thrombocytopenia, and elevated serum IgA level as significant adverse prognostic factors for PFS (P < .001, P < .001, and P = .002). Based on these findings, we constructed new prognostic model for the younger group, based on three adverse factors. We classified the patients into two risk groups: low risk (no or 1 adverse factor) and high risk (2 or 3 adverse factors). This new model for younger patients with AITL showed that both OS and PFS were significantly related to the level of risk (P < .0001). In summary, this study showed that, among younger patients with AITL, an EBER+ status significantly improved prognosis compared to an EBER- status. Our new prognostic model should be applicable to younger patients with AITL.

Clinicopathological Study of 30 Cases of Peripheral T-cell Lymphoma with Hodgkin and Reed-Sternberg-like B-cells from Japan.

The presence of Hodgkin and Reed-Sternberg (HRS)-like B-cells in peripheral T-cell lymphoma (PTCL) is rare and its clinicopathological features still remain unclear. Here, we describe 30 cases of PTCL with HRS-like B-cells from Japan. Twenty-three cases (77%) presented evidence of follicular T-helper phenotype (TFH) derivation: 12 were angioimmunoblastic T-cell lymphoma and 11 PTCL with TFH phenotype (PTCL-TFH). The remaining seven cases were diagnosed as PTCL, not otherwise specified (PTCL-NOS). Epstein-Barr virus (EBV) reactivation was detected in 25 cases (83%), but HRS-like B-cells were EBER in only 20 cases (67%). The median age at diagnosis was 77 years (range, 39-91 y), including 24 patients (80%) were older than 60 years of age. Most of the patients presented at an advanced clinical stage and were associated with higher risk according to the International Prognostic Index. The 3-year overall and progression-free survival rates were 44% and 27%, respectively. No significant clinicopathological differences were detected between PTCL-TFH, PTCL-NOS and the angioimmunoblastic cases. Cases with EBER HRS-like B-cells were associated with inferior overall and progression-free survival compared to those with EBER HRS-like B-cells, but the difference was not significant. In conclusion, HRS-like B-cells were found in a subset of T-cell lymphomas, especially in association with the TFH phenotype and EBV reactivation. These cells have a tendency to affect elderly patients and to be associated with advanced clinical stages and dismal prognosis. The EBV status of HRS-like B-cells does not seem to affect the clinicopathological features of this group of PTCLs.

MUM-1 expression differentiates AITL with HRS-like cells from cHL.

MUM1 is a member of the interferon regulatory factor family of transcription factors. It is normally expressed in plasma cells, late B cells, and activated T cells, and has been described in several B-cell malignancies and some T-cell neoplasms. The aim of our study was to evaluate the role of MUM-1/IRF4 protein in differentiating angioimmunoblastic T cell lymphoma (AITL) with Hodgkin/Reed-Sternberg (HRS)-like cells from cHL. We identified 12 cases of AITL with HRS-like cells and 24 cases of cHL from March 2013 to November 2014. IHC for MUM-1/IRF4 protein was performed on the tissue of these cases and some relevant positive and negative controls. MUM-1 was expressed in HRS-like cells and some neoplastic T-cells in AITL with HRS-like cells (12/12, 100%) and formed the rosettes around the HRS-like cells (12/12, 100%), expressed in HRS cells in classic Hodgkin Lymphoma (cHL) (24/24, 100%) and just one case formed rosettes around the HRS cells (1/24, 4.2%). Based on the results, MUM-1 could be a useful marker for the differential diagnosis between AITL with HRS-like cells and cHL.

Angioimmunoblastic T-cell lymphoma in Taiwan shows a frequent gain of ITK gene.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma (PTCL) of follicular helper T-cell origin and is rare in Taiwan. There are overlapping features of AITL and peripheral T-cell lymphoma with a follicular growth pattern (PTCL-F). Around one fifth of PTCL-F exhibits t(5;9)(q33;q22)/ITK-SYK chromosomal translocation, which is essentially absent in AITL. We retrospectively investigated 35 cases of AITL from Taiwan with histopathology review, immunohistochemistry, in situ hybridization for Epstein-Barr virus (EBV) and fluorescence in situ hybridization (FISH) for t(5;9)(q33;q22)/ITK-SYK and correlated the results with overall survival. Twenty-six cases of not otherwise specified PTCL (PTCL-NOS) were also examined by FISH for comparison. Most AITL patients were male (69%) and elderly (median age at 67 years) with frequent bone marrow involvement (53%), high Ann Arbor stages (77%), and elevated serum lactate dehydrogenase (68%). Most cases (80%) showed a typical CD4+/CD8- phenotype and in 90% cases there were scattered EBV-positive B-cells (less than 10% cells). None of these cases showed t(5;9)(q33;q22)/ITK-SYK translocation by FISH. Gain of ITK and SYK gene was identified in 38% and 14% tumors, respectively, but both were not associated with overall survival. Performance status < 2 was associated with a better outcome but not the other clinicopathological factors. All PTCL-NOS cases were negative for ITK-SYK translocation with similar rates (38% and 12%, respectively) of gains at ITK and SYK loci as that of AITL. In this so far the largest series of AITL from Taiwan, we reported the clinicopathological features and FISH findings on ITK and SYK genes. We confirmed the absence of t(5;9)(q33;q22)/ITK-SYK translocation, which may serve as an additional differential diagnostic tool from PTCL-F when present. PTCL-NOS shared a similar pattern of ITK and SYK gains with AITL. More studies are warranted to elucidate the roles of SYK and ITK and other genes in the lymphomagenesis of AITL in Taiwan.

Epstein-Barr virus present in T cells or B cells shows differential effects on hemophagocytic symptoms associated with outcome in T-cell lymphomas.

Non-specific peripheral (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) frequently show Epstein-Barr virus (EBV) expression in lymphoma or bystander B cells. However, whether EBV localization affects clinicopathologic features is unclear. We correlated EBV localization with clinicopathologic findings in PTCL-NOS (n = 63) and AITL (n = 26). PTCL-NOS showed EBV+ in 41%, with 22% in lymphoma T cells (T-EBV) and 19% in bystander B cells (B-EBV), and more EBV+ cells in T-EBV cases (39.3% vs. 11.8%, p = 0.003). Compared to B-EBV cases, T-EBV PTCL-NOS had higher rates of type II EBV latency (p = 0.003), leukopenia (p = 0.020) and hemophagocytosis (p = 0.061), which predicted a poor outcome (p < 0.001). In contrast, 88% of AITLs were EBV+, exclusively in B cells. EBV+ cases showed lower rates of hemophagocytosis (p = 0.006), but this was insignificant for prognosis. Therefore, hemophagocytic symptoms in PTCL-NOS are much more tightly associated with T-EBV and carry poor prognoses. In contrast, hemophagocytosis in AITL is correlated with EBV-, but is not significant for outcome.

In immunocompromised patients, Epstein-Barr virus lymphadenitis can mimic angioimmunoblastic T-cell lymphoma morphologically, immunophenotypically, and genetically: a case report and review of the literature.

The development of lymphomas and solid malignancies in association with immunosuppression is a well-documented occurrence in the medical literature. We report the case of a young man who developed progressive diffuse lymphadenopathy with associated extremely high levels of serum Epstein-Barr virus in the setting of chronic immunosuppressive treatment of glomerulonephritis. Excisional biopsy of a right inguinal node revealed a sclerosing process with the morphologic appearance of angioimmunoblastic T-cell lymphoma with a CD3(+), CD4(+) immunophenotype. In situ hybridization of Epstein-Barr virus-encoded RNA was positive. Molecular probe studies demonstrated a clonal T-cell population. Upon reduction of immunosuppression, the patient's lymphadenopathy and Epstein-Barr virus titer have resolved without recurrence over 2 years time. This case demonstrates that a benign Epstein-Barr virus-associated process can mimic angioimmunoblastic T-cell lymphoma and should be considered particularly in the setting of immunosuppression, emphasizing the need for close communication with the treating physician in the interpretation of lymph node biopsies.

Three different expression patterns of T-bet in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) exhibits a multifaceted clinical picture and distinct architectural patterns that correlate with disease progression and the number of neoplastic cells. In this study we investigated the expression of the transcription factor T-bet and correlated it with the architectural patterns in 29 cases of AITL. Double immunolabelings for T-bet, CD20, CD3 or PD1 revealed the following patterns: predominant T-bet expression by neoplastic T-cells (A), by aggregates of small B-cells (B) or by B-immunoblasts (C). The majority of cases of AITL pattern II showed a T-bet expression pattern B (6/8 cases), while the majority of those with pattern III exhibited the T-bet pattern A (11/21 cases). We propose that T-bet expression by B-cells represents a T-cell independent immune response trying to cope with opportunistic infections, while T-bet expression by neoplastic T-cells is linked to the introduction of a Th17 response responsible for the immunologic derangements characteristic of AITL.

Evaluation of cutaneous angioimmunoblastic T-cell lymphoma.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) accounts for 18% of peripheral T-cell lymphomas worldwide. Skin involvement occurs in up to 50% of patients but poses a diagnostic dilemma because of the limited number of reported cases and subsequent lack of established diagnostic criteria. OBJECTIVE: The purpose of this review is to examine common clinical, histologic, and molecular findings in cases of AITL with the hope of improving the diagnostic accuracy of this challenging condition. METHODS: We present a case of AITL and conducted a review of the literature. RESULTS: The common clinical and histologic features in cases of AITL are nonspecific. However, newer immunohistochemical stains and gene rearrangement studies appear very promising at improving diagnostic capabilities. LIMITATIONS: There was a paucity of reported cases of AITL in the literature, and this review is retrospective. CONCLUSION: AITL presents with nonspecific clinical and histologic findings, but immunohistochemical stains and gene rearrangements can help establish the diagnosis.

[Clinicopathologic study of 963 cases of mature T-cell and natural killer/T-cell lymphoma with respect to 2008 WHO classification of lymphoid neoplasms].

OBJECTIVE: To study the clinicopathologic features of various types of mature T-cell and natural killer (NK)/T-cell lymphoma in Guangdong, China, with respect to the 2008 WHO classification of lymphoid neoplasms. METHODS: Eleven hundred and thirty-seven (1137) cases of mature T-cell or NK/T-cell lymphoma diagnosed during the period from 2002 to 2006 in Guangzhou area were retrieved. The clinical data, histologic features and immunohistochemical findings were reviewed by a panel of experienced hematopathologists. Additional immunostaining was performed if indicated. The cases were re-classified according to the 2008 WHO classification of lymphoid neoplasms. RESULTS: Nine hundred and sixty-three (963) cases fulfilled the diagnostic criteria of mature T-cell or NK/T-cell lymphoma and accounted for 20.1% of all cases of lymphoma encountered during the same period (963/4801). A predominance of extranodal involvement was noted in 644 cases (66.9%), while 319 cases (33.1%) showed mainly nodal disease. The prevalence of various lymphoma subtypes was as follows: peripheral T-cell lymphoma, unspecified (PTCL, NOS) 293 cases (30.4%), extranodal NK/T-cell lymphoma, nasal type 281 cases (29.2%), anaplastic large cell lymphoma (ALCL) 198 cases (20.6%), and angioimmunoblastic T-cell lymphoma (AILT) 46 cases (4.8%). The male-to-female ratio was 1.99. The median age of the patients was 44 years, with the peak age of PTCL, NOS, extranodal NK/T-cell lymphoma, nasal type and AILT being 55 to 64 years, 25 to 54 years and 65 to 74 years, respectively. ALK-positive ALCL occurred more frequently in young age, while the ALK-negative ALCL cases occurred mainly in the elderly. CONCLUSIONS: Extranodal lesions predominate in mature T-cell and NK/T-cell lymphomas occurring in Guangzhou area. There is a male predominance and the overall incidence shows no increasing trend with age of the patient. The peak age of various subtypes however varies. The most common subtype was PTCL, NOS, followed by extranodal NK/T-cell lymphoma, nasal type, ALCL and AILT. The relatively frequent occurrence of extranodal NK/T-cell lymphoma, nasal type in Guangdong area is likely associated with the high incidence of Epstein-Barr virus infection there.

Diffuse large B-cell lymphoma in patient after treatment of angioimmunoblastic T-cell lymphoma.

Relatively few cases of Epstein-Barr (EBV)-positive B-cell lymphomas arising in patients with angioimmunoblastic T-cell lymphoma (AITL) have been reported. We report a case of AITL in which diffuse large B-cell lymphoma arose 13 months after the initial diagnosis of AITL. In a 36-year-old female patient, evaluated for moderate leukocytosis, peripheral and abdominal lymphadenopathy AITL was diagnosed in March 2008, based on results of fine-needle aspiration cytology (FNAC) of the enlarged cervical and supraclavicular lymph nodes. The diagnosis was also confirmed by immunophenotyping and histopathology of the cervical lymph nodes. The patient initially recieved FED chemotherapy (fludarabine, cyclophosphamide, dexamethasone) followed by elective autologous hematopoietic stem cell transplantation. In April 2009 the patient was hospitalized because of fever, pancytopenia, hyperbilirubinemia and peripheral lymphadenopathy. The FNAC of the enlarged cervical lymph nodes was performed again, but this time the smears were composed of polymorphous population of lymphocytes with the predomination of large cells, CD20+ on immunocytochemical stains. The immunophenotyping confirmed a predomination of monoclonal mature B-cells. Patient had high number of EBV DNA copies in plasma and serologic testing revealed increased titers of EBV VCA IgG and EBV EBNA IgG. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) was then administered, resulting in good partial response of the disease. Reduced intensity allogeneic stem cell transplantation performed thereafter, resulted in complete remission of the disease. AITL is a rare lymphoproliferative disorder in which the neoplastic T-cells represent the minority of the lymph node cell population and almost all cases harbor EBV-infected B-cells. Various authors postulated that immunodeficiency in AITL patients together with immunosuppressive effects of cytotoxic drugs, may be responsible for EBV-induced proliferation of latently or newly EBV-infected B-cells with eventual clonal selection and progression to aggressive B-cell lymphoma.

Differential diagnosis of angioimmunoblastic T-cell lymphoma with seropositivity for anti-HTLV antibody from adult T-cell leukemia/lymphoma.

Angioimmunoblastic lymphoma (AITL) is a nodal peripheral T-cell lymphoma characterized by a proliferation of arborizing vessels and hyperplastic follicular dendritic cells as well as a polymorphous lymphoid infiltrate including neoplastic cells with clear cytoplasm. Adult T-cell leukemia/lymphoma (ATLL) is caused by the retrovirus human T-cell leukemia virus type I (HTLV-I), and the neoplastic cells are usually large and pleomorphic. Recently, a rare morphologic variant of ATLL with AITL-like features has been reported. Here, we presented a case of peripheral T-cell lymphoma with morphological features of AITL in Taiwan, a country non-endemic for HTLV, and the patient was seropositive for anti-HTLV antibody, which raised the possibility of ATLL with AITL-like features. Immunohistochemically, there were hyperplastic follicular dendritic meshworks by CD21 immunostaining, and the neoplastic cells expressed CD10, programmed death-1, and CXCL13. Furthermore, Southern blot analysis using DNA extracted from the nodal tissue was negative for HTLV-I proviral integration. Our investigations indicated that in an HTLV-I non-endemic area, a peripheral T-cell lymphoma with typical morphologic and immunophenotypic features of AITL could be confidently diagnosed as AITL even if the patient was seropositive for anti-HTLV antibody.

Epstein-Barr virus-positivity in tumor has no correlation with the clinical outcomes of patients with angioimmunoblastic T-cell lymphoma.

BACKGROUND/AIMS: Epstein-Barr virus (EBV) is involved in the pathogenesis of angioimmunoblastic T-cell lymphoma (AILT), but its precise role and prognostic impact are not clear. This study aimed to evaluate the incidence of EBV-postitivity in the tumor and bone marrow (BM) samples from AILT patients, and their correlations with the clinical variables and patient survival. METHODS: Seventy AILT cases were identified over a period of 8 years. Twenty seven cases were investigated for their EBV tumor status, and 10 BM samples of these patients were investigated for their EBV status with using in situ hybridization (ISH). EBV PCR was performed for the BM mononuclear cells in 8 cases. RESULTS: Among the 27 tumor specimens, ten (37%) were EBV-positive. Only CD20-negativity in tumor correlated with the EBV-positivity (p = 0.035). In 13 (48%) patients, gross tumor involvement was recognized by hematoxylin-eosin staining at the time of diagnosis. Among the 10 patients who had additional BM slides available, there were 3 with BM involvement, and none showed EBV positive results on ISH. EBV PCR of the BM mononuclear cells revealed one-positive case among 8 patients. This patient was negative for both BM involvement and EBV ISH. The median overall survival of the 25 treated patients was 48.9 months (95% CI: 18.6 approximately 79.2 months). Neither overall survival nor progression-free survival was related with EBV-positivity of the tumor. CONCLUSIONS: EBV-positivity of tumor had no impact on the prognosis of AILT patients.

Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients.

We retrospectively analyzed 77 patients with pathologically diagnosed angioimmunoblastic T-cell lymphoma from a single city. There were 43 men and 34 women; the median age was 64.5 years (range, 30-91 yr). Average time between first symptoms of the disease and diagnosis was 3.6 months. At diagnosis, peripheral nodes were present in all but 1 patient, and were generalized in 90% of cases. Constitutional symptoms were reported in 77% of cases and spleen enlargement in 51%. A cutaneous eruption--morbilliform, urticarial, or more polymorphic--was present in 45% of patients; in one-third of them, the eruption occurred after drug administration. Other clinical manifestations included pleuritis (22%); arthralgia or arthritis (17%); ear, nose, and throat involvement (14%); central or peripheral neurologic manifestations (10%); and ascites (5%). Most patients presented with advanced disease at diagnosis (bone marrow involvement in 60% of cases). The main laboratory abnormalities were elevated lactate dehydrogenase levels (71%), inflammatory syndrome (67%), hypergammaglobulinemia (50%), anemia (51%), and lymphopenia (52%). Auto- or disimmune manifestations were reported in one-third of patients: autoimmune hemolytic anemia was present at diagnosis in 19% of patients and thrombocytopenic purpura in 7%. Documented vasculitis was described in 12% of cases. Clonality was analyzed in lymph nodes in 47 patients: T-cell and B-cell clones were found in 45 (96%) and 20 (45%) patients, respectively. Chromosomal abnormalities were identified in 62% of cases: trisomies 3, 5, 18, 19, additional X chromosome, and deletion of chromosome 7 were the most common abnormalities. The current study underlines the diversity of presenting manifestations of angioimmunoblastic T-cell lymphoma.

Epstein-Barr virus genome level, T-cell clonality and the prognosis of angioimmunoblastic T-cell lymphoma.

BACKGROUND AND OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AILT) is a peripheral T-cell tumor of unknown etiology with variable biological and clinical presentations. Previous clonality studies have shown heterogeneous clonal restrictions of B- and T-cell populations in this tumor. AILT is characterized by the presence of increased numbers of Epstein-Barr virus (EBV) infected cells. The aim of this study was to clarify the correlation between clonality, EBV and prognosis. DESIGN AND METHODS: Frozen material from 59 cases of AILT was used for DNA isolation and gene analysis by Southern blotting. A real-time polymerase chain reaction was used to quantify the amount of EBV-DNA in the tissue. Survival data were retrieved from clinical records. RESULTS: Clonal T cells were found in 15/50 and clonal B-cells in 2/50 tumors, using Southern blot analysis. Bands of EBV-W were found in 10/50 tumors. Survival rate did not correlate with either T-cell clonality (p=0.84), or presence of EBV-infected cells (p=0.84). The EBV-DNA copy number in EBV-infected tissue did not correlate with disease progression (p=0.87). The survival rate and clinical status according to the international prognostic index (IPI) did not correlate with T-cell clonality status or EBV infection. INTERPRETATION AND CONCLUSIONS: AILT remains a heterogeneous disease with clinical behavior that varies irrespective of the genomic parameters investigated.

Epstein-Barr virus load correlating with clinical manifestation and treatment response in a patient with angioimmunoblastic T-cell lymphoma.

Epstein-Barr virus (EBV)-associated lymphoma may arise secondary to angioimmunoblastic T-cell lymphoma (AITL). The prognosis is poor despite chemotherapy and experimental therapies. We report on a 40-year-old woman with AITL without obvious immunodeficiency in which EBV-associated lymphoma developed. The occurrence and size of enlarged lymph nodes correlated strongly with the EBV load in serum (EBVL). Treatment with valacyclovir at the early stage resulted in a drastic more than 3 log10 decrease of EBVL and complete remission. However, valacyclovir had to be stopped after 6 months due to side effects, and the lymphoma reoccurred 3 months later associated with increasing EBVL. Eventually started cytotoxic chemo- and anti-CD20 therapy resulted only in partial remission. The lymphoma progressed and 33 months after it was diagnosed the patient died. This case report demonstrates the close association of EBVL and AITL and a beneficial effect of antiviral therapy at an initial stage of disease manifestation.

T- and B-cell clonality and frequency of human herpes viruses-6, -8 and Epstein Barr virus in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (T-AIL) is a peripheral T-cell lymphoma of unknown etiology. Previous clonality studies have shown a heterogeneous composition of this disease with varying restrictions of B- and T-cell populations in the tumour. For the first time in a single study and in the same pathological materials, we have analysed, lymphoid cell clonality and occurrence of human herpes viruses and Epstein Barr virus. Of 18 cases 12 (66.6%) had clonal T- and three (16.6%) had clonal B-cells. Presence of the lymphotropic viral genome of HHV6 was detected in four of 18 lymph node biopsies from T-AIL patients (22%), all were TCRgamma clonal. No HHV8 were found. Epstein Barr genome was found in 40% of cases. There was no significant association between T-cell clonality and HHV-6 or EBV infection, or between B-cell clonality and any virus infection. We conclude that T-AIL is a biologically and clinically heterogeneous entity whose true nature remains to be clarified.

Angioimmunoblastic T-cell lymphoma associated with an antibody to human immunodeficiency virus protein.

A 58-year-old man was admitted with generalized lymphadenopathy. On admission, the patient showed polyclonal hyper-gammopathy in a blood examination, positive results in the direct/indirect Coombs test, and an elevated cold agglutinin titer. Autoimmune thrombocytopenia with a high level of platelet-associated immunoglobulin G complicated the patient's condition. An enzyme immunoassay kit for human immunodeficiency virus (HIV) recombinant proteins p24, gp41, and gp36 showed positive results. Western blot analysis showed the presence of antibodies cross-reacting with HIV p24 gag protein. HIV RNA was not detected by means of a reverse transcriptase-polymerase chain reaction assay, so the patient was not an HIV carrier. Angioimmunoblastic T-cell lymphoma (AILT) was diagnosed on the basis of lymph node biopsy specimens. We speculated that in this case some of the numerous subtypes of polyclonal gamma globulin had coincidentally cross-reacted with HIV p24. Cross-reactive phenomena with HIV in patients with systemic lupus erythematosus have been well investigated, but to our knowledge our patient is the first case of such cross-reactivity involving AILT. Physicians should pay close attention to serologic tests to determine whether the patient truly is a viral carrier.