Acquired immunodeficiency syndrome-associated T-cell lymphoma: evidence for human immunodeficiency virus type 1-associated T-cell transformation.

The majority of lymphomas in the setting of acquired, iatrogenic, or congenital immunodeficiencies are B-cell lymphoproliferations. We describe a rare T-cell lymphoma in a fulminantly ill patient infected with human immunodeficiency virus type 1 (HIV-1). The T-cell nature of the process was defined genotypically (monoclonal T-cell receptor beta-chain [CT beta] rearrangement) and phenotypically (CD45RO+, CD4+, CD5+, CD25+, CD8-, CD3- and negative for a variety of B-cell and monocyte markers). The CD4+, CD25+ (interleukin-2 receptor [IL-2R]) phenotype with production of IL-2 and IL-2R RNA is analogous to human T-lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATLL); however, no HTLV-1 could be detected. Southern blot analysis did demonstrate monoclonally integrated HIV-1 within the tumor genome. Furthermore, the tumor cells were producing HIV p24 antigen as shown by immunohistochemistry. This is the first case of acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphoma in which HIV-1 infection may have played a central role in the lymphocyte transformation process.     

Microenvironment of adult T-cell leukemia/lymphoma-associated nodal lesions

Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with the retrovirus, human T-cell leukemia virus type I (HTLV-I). In a previous series of studies, our group and others characterized the histopathological changes in HTLV-I-associated lymph node lesions. In addition to the pleomorphic and anaplastic large cell types of typical ATL lymphoma, we identified lymph nodes with an unusual Hodgkin’s disease-like histology (Hodgkin-like ATLL) in HTLV-I-positive patients, with Hodgkin-like ATLL showing prodromal clinical features. We also reported HTLV-I-associated lymphadenitis, characterized by non-neoplastic HTLV-I-associated lymph node lesions. It has become clear that the biological and clinical behavior of malignant lymphoma is not only determined by the properties of the lymphoma cells themselves, but also largely by the interaction of these cells with their nonmalignant microenvironment. In this review, we discuss the pathological variations of microenvironments, which are important for clarification of the histological features associated with HTLV-I.     

A Rare Case of Adult T Cell Leukemia/Lymphoma: Clinicopathological Correlation with Autopsy Confirmation

Adult T cell leukaemia/lymphoma (ATLL) is a rare T lymphoproliferative disorder which is etiologically linked with human T cell lymphotropic virus type-1 (HTLV-1). HTLV-1 is endemic in Japan, Caribbean and Africa. The highest incidence of ATLL is in Japan although sporadic cases have been reported elsewhere in the world. We describe a case of ATLL with an unusual presentation with clinic-pathological correlation and autopsy confirmation. A 56 year old male was referred to Command Hospital (Southern Command) for an incidental finding of lymphocytosis on a routine Hemogram. Clinical examination did not reveal hepatosplenomegaly, lymphadenopathy, jaundice or skin lesions. Laboratory investigations showed lymphocytosis with predominance of atypical lymphomonocytoid cells. Immunophenotyping of the bone marrow mononuclear cells showed positivity for CD45, CD2, CD3, CD4, CD5 and negative for CD7, CD8, CD13, CD33, CD19, which is characteristic of ATLL phenotype. Clonality was confirmed by PCR for TCR gene rearrangement on post mortem tissue. He succumbed to his illness after 40 days of initial presentation and 16 days of being diagnosed as ATLL. Here, we discuss the pathogenesis and characteristics of ATLL with clinico-pathological correlation and autopsy confirmation.     

Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy: A Case Report

Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity.We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism.Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control.This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity.     

Primary adrenal adult T-cell leukemia/lymphoma: a case report and review of the literature

Primary adrenal lymphoma (PAL) is very rare; the majority of cases reported previously were of B-cell origin. We report a rare case of primary adrenal adult T-cell leukemia/lymphoma (primary adrenal ATLL). ATLL is a highly aggressive T-cell type non-Hodgkin's lymphoma and etiologically associated with human T-cell lymphotropic virus 1 (HTLV-1). Most ATLL patients present with leukemia and widespread lymphadenopathy. A 37-year-old Japanese woman presented with back pain in January 2004. Examination showed no peripheral lymphadenopathy, circulating lymphoma cells, hepatosplenomegaly, and skin lesions. Imaging studies demonstrated large adrenal masses bilaterally. Subsequently, she underwent open adrenal biopsy and pathological diagnosis was confirmed as T-cell lymphoma. The serum antibody to HTLV-1 was positive. Southern blot analysis detected monoclonal integration of proviral DNA of HTLV-1 into host genome in the biopsy specimen. The diagnosis of ATLL arising in adrenal glands was established. Despite repeated systemic chemotherapy, the patient died of progressive disease in December 2004. ATLL could primarily involve the adrenal gland and this disease entity should be included in the differential diagnosis of adrenal mass lesions.     

Transformation of T-cell large granular lymphocyte leukaemia into a high-grade large T-cell lymphoma

We describe a case of T-cell large granular lymphocyte (LGL) leukaemia that transformed into a large-cell T-cell lymphoma 11 years from diagnosis. A 29-year-old asymptomatic female presented in 1989 with lymphocytosis, neutropenia and mild bone marrow infiltration. The circulating cells were LGL with a CD2+, CD3+, CD8+, CD4-, CD16+, CD56+, CD57- phenotype. In August 2000, she developed fever, a large submandibular mass and hepatosplenomegaly. Biochemistry showed abnormal liver function tests and raised lactate dehydrogenase (LDH) levels. A serological screen for Epstein-Barr virus, cytomegalovirus, human T-lymphotropic virus-I, human herpes virus (HHV)-6 and HHV-7 was negative. Histology of the mass was consistent with the diagnosis of peripheral T-cell lymphoma composed of large cells, and immunohistochemistry showed that the lymphoma cells had a phenotype identical to the mature LGL. Molecular analysis with the polymerase chain reaction (PCR) demonstrated rearrangement of the T-cell receptor (TCR) gamma-chain gene with a band of identical size in both bone marrow mature LGL and lymph node cells. The patient was treated with CHOP (cyclophosphamide, vincristine, doxorubicin and prednisolone), resulting in the disappearance of the mass and improvement of the hepatosplenomegaly, LDH and liver abnormalities. She underwent splenectomy, and spleen histology showed involvement by T-cell LGL leukaemia with no evidence of transformation. This case illustrates that transformation or Richter syndrome may occur in a minority of patients with T-cell LGL leukaemia, a disease that has a benign clinical course in most cases. This is the first case documented by molecular methods of the transformation of the pre-existing clone.     

CD20- and CD56-Positive T-Cell Large Granular Lymphocyte Leukemia in a Human T-Cell Leukemia Virus Type 1 Carrier

A 60-year-old man was diagnosed with asymptomatic T-cell granular lymphocyte (T-LGL) leukemia in September 2006. He was serologically positive for human T-cell leukemia virus type 1 (HTLV-1). However, monoclonal integration of the HTLV-1 genome was not detected in the peripheral blood, suggesting that HTLV-1 did not contribute to the pathogenesis of T-LGL leukemia in the present case. Phenotypically, neoplastic cells of our case were CD3+, CD4*, CD8+, CD16-, CD56+, CD57*, and T-cell receptor (TCR) alphabeta+. They also coexpressed CD20 antigen with weak intensity. This represented a unique case of T-LGL leukemia showing a typical clinical and phenotypic features.     

HTLV-1 unrelated adult T-cell leukemia/lymphoma with unique phenotype and karyotype

We describe a unique case of adult T-cell leukemia/lymphoma (ATL). The patient had typical clinicohematological features as ATL, but showed a lack of antibody to human T-cell leukemia virus type-1 (HTLV-1) and was negative for HTLV-1 proviral DNA in the peripheral mononuclear cells by means of polymerase chain reaction. The phenotype of tumor cells revealed CD7+, CD5+, CD2+, CD3+, WT31-, TcR delta 1-, CD4-, CD8-, CD25-, and the karyotype showed a 5q-, t(12;18). HTLV-1 unrelated ATL is very rare, and the karyotype as in our case has not been reported previously.     

Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8(+) T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8(+) T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL.     

Human T-cell lymphotropic virus type I associated adult T-cell leukaemia/lymphoma in Taiwan Chinese

Twenty-five Chinese patients with human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukaemia/lymphoma (ATLL) were identified in Taiwan. No patients had been outside Taiwan and none were descendants of Japanese heritage. Their ages ranged from 28 to 71 years. There were 17 men and eight women. Main clinical and laboratory features at presentation were lymphadenopathy (16), skin lesions (11), hepatosplenomegaly (11), pulmonary lesions (11), hypercalcaemia (10) and bone marrow infiltration (14). Peripheral blood was characterized by leucocytosis with presence of pleomorphic abnormal lymphocytes but rare anaemia or thrombocytopenia. The clinical subtypes were acute in 15, chronic in three, smouldering in one, and lymphoma type in six. The immunophenotypes of the ATLL cells were characterized by the expression of CD2+, CD4+, CD7-, CD8- and CD25+. The overall prognosis was poor with a median survival of 5 months. The acute form had a significantly shorter survival (2 months) than lymphoma type (13 months). Susceptibility to various infections was common. Pulmonary complications accounted for 73% of the causes of death. The clinicopathologic features of ATLL in Taiwan are indistinguishable from those in HTLV-I endemic areas. The present series adds to the knowledge of the worldwide pattern of the disease.     

Human T-cell lymphotropic virus type 1 (HTLV-1) and lymphoid malignancies in Dominica: a seroprevalence study

Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in certain regions of the world where it is associated with lymphoid malignancies. Herein we aim to describe the seroprevalence of HTLV-1 in lymphoid malignancies in Dominica. We carried out a 10-year retrospective study of histologically proven hematologic malignancies and HTLV-1 seropositivity at the Princess Margaret Hospital, Dominica. Ninety-eight cases were reviewed (59% males, 41% females), ranging in age from 3 to 91 years. HTLV-1 was seropositive in 38.6% (31/80) of all hematologic malignancies. Three of 6 cases of Hodgkin disease (50%), 16 of 36 (44.4%) of non-Hodgkin lymphoma, and 3 out of 8 unclassified lymphomas (37.5%) were seropositive; all 6 cases (100%) of acute adult T-cell leukemia/lymphoma (ATLL) were seropositive. One case each of chronic lymphocytic leukemia and myeloproliferative disorder was seropositive. HTLV-1-seropositive lymphomas presented at a younger age than did seronegative cases. Thus, HTLV-1 is significantly associated with lymphoid malignancies in Dominica, and further studies are needed before a causal relationship with Hodgkin disease can be established.     

C7a, a biphosphinic cyclopalladated compound, efficiently controls the development of a patient-derived xenograft model of adult T cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd(2) [S(-)C(2), N-dmpa](2) (μ-dppe)Cl(2)}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.     

The distribution of CD45R, CD29 and CD45RO (UCHL1) antigens in mature CD4 positive T-cell leukaemias

We have studied the expression of antigens characterizing functional T-cell subsets in 32 CD4+ mature T-cell leukaemias. In this analysis we used two monoclonal antibodies (McAb) of the CD45R group (2H4 and GRT22) which have been shown to identify the 'native/virgin' T-cell population that functions as 'suppressor-inducer' cells in vitro, and two McAb, CD29 (4B4) and CD45RO (UCHL1), which characterize non-identical 'memory' cells that proliferate in response to soluble recall antigens and provide help in antigen-specific IgG synthesis. Four groups of CD4+ cases were identified according to this reactivity: (a) 15 CD45R+, CD29+; (b) 13 CD45R-, CD29+; (c) three CD45R-, CD29-; and (d) one case only CD45+, CD29-. The high incidence of coexpression of CD45R and CD29 (47% of cases) is a new finding which contrasts with the mutual exclusion of these antigens on normal CD4+ T-lymphocytes. There was no correlation between subset phenotypes and pathological disease entities. None of the six cases of adult T-cell leukaemia/lymphoma (ATLL), which is known as a disorder of activated 'suppressor-inducer' cells, had the 'expected' CD45R+, CD29- phenotype. Reactivity with UCHL1 showed a good correlation with CD29 in the CD45R- CD29+ cases which included three with ATLL. These results may help in the further characterization of T-cell malignancies according to functional subgroups and may clarify further the role of T-differentiation antigens in health and disease.     

Adult T-cell leukaemia and lymphoma: report of two cases and a brief review of the literature

Human T-cell lymphotropic virus type 1 (HTLV-1) can cause adult T-cell leukaemia/lymphoma (ATLL). Two patients originating from the Caribbean area with ATLL are described. The first patient developed respiratory insufficiency due to acute T-cell leukaemia. The diagnosis was suspected because of characteristics of abnormal lymphocytes in the blood smear. The second patient had lymphadenopathy and developed severe hypercalcaemia. Both patients were typical cases of ATLL. The pathogenesis, clinical manifestations, pitfalls and treatment of this intriguing disease are discussed.     

Adult T-cell leukaemia/lymphoma-like human T-cell leukaemia virus-1 replication in infective dermatitis

Adult T-cell leukaemia/lymphoma (ATLL) is a malignant T-cell proliferation that occurs in 3-5% of individuals infected with human T-cell leukaemia virus-1 (HTLV-1). HTLV-1 infection is also linked to the development of infective dermatitis (ID), an exudative dermatitis of children that has been proposed as a cofactor of ATLL. Here, HTLV-1 replication was investigated over time in a girl with ID and multiparasitic infestation including strongyloidiasis, a disease also known to predispose HTLV-1 carriers to ATLL. Quantitative polymerase chain reaction (PCR) revealed extremely high proviral loads. During the 2-year period of the present study, the proportion of circulating infected cells ranged between 12% and 36%. Quadruplicate linker-mediated PCR amplification of HTLV-1 flanking sequences identified a pattern of extensive and persistent oligoclonal expansion of infected lymphocytes. As viral loads, both the number and the degree of infected T-cell expansion were independent of treatment or clinical signs. However, the temporal fluctuation of proviral loads correlated significantly with the degree of infected T-cell expansion, but not with the overall number of detected clones. This pattern of HTLV-1 replication over time is very different from that observed in asymptomatic carriers and reminiscent of that observed in ATLL, a result consistent with the proposal of ID as an ATLL cofactor.     

PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2–3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.     

Recent Advances in Therapeutic Approaches for Adult T-cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia/lymphoma virus type 1 (HTLV-1). ATLL occurs in approximately 3%–5% of HTLV-1 carriers during their lifetime and follows a heterogeneous clinical course. The Shimoyama classification has been frequently used for treatment decisions in ATLL patients, and antiviral therapy has been reportedly promising, particularly in patients with indolent type ATLL; however, the prognosis continues to be dismal for patients with aggressive-type ATLL. Recent efforts to improve treatment outcomes have been focused on the development of prognostic stratification and improved dosage, timing, and combination of therapeutic modalities, such as antiviral therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, and molecular targeted therapy.