Adult T-cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma (ATLL) is a mature T-cell neoplasm of post-thymic lymphocytes aetiologically linked to the human T-cell lymphotropic virus, HTLV-I, and with a distinct geographical distribution. The disease manifests with leukaemia in greater than two thirds of patients, while the remaining patients have a lymphomatous form. According to the disease manifestations, various forms which differ in clinical course and prognosis have been recognised: acute, chronic, smouldering and lymphoma. Organomegaly, skin involvement, circulating atypical lymphocytes ("flower" cells) with a CD4+ CD25+ phenotype and hypercalcaemia are the most common disease features. The diagnosis should be based on a constellation of clinical features and laboratory investigations. The latter comprise: lymphocyte morphology, immunophenotype, histology of the tissues affected in the pure lymphoma forms and serology or DNA analysis for HTLV-I. The differential diagnosis of ATLL includes other mature T-cell neoplasms such as T-cell prolymphocytic leukaemia (T-PLL), Sézary syndrome (SS), peripheral T-cell lymphomas and occasionally healthy carriers of the virus or Hodgkin disease. The clinical course is aggressive with a median survival of less than 12 months in the acute and lymphoma forms. Despite major advances in understanding the pathogenesis of the disease, management of these patients remains a challenge for clinicians as they do not respond or achieve only transient responses to therapies used in high-grade lymphomas. The use of antiretroviral agents such as zidovudine in combination with interferon-alpha, with or without concomitant chemotherapy, has shown activity in this disease with improvement in survival and response rate. Consolidation with high dose therapy and autologous or allogeneic stem-cell transplantation should be considered in young patients.     

Monoclonal antibody HML-1 reactivity with adult T-cell leukaemia/lymphoma and other lymphomas

Human T-cell leukaemia/lymphoma virus type 1 (HTLV-1), a causative virus of adult T-cell leukaemia/lymphoma (ATLL), is known to be transmitted by breast-feeding. Using a monoclonal antibody HML-1 which labels human intestinal intra-epithelial T lymphocytes, we have immunohistochemically examined ATLL tissues in order to evaluate the possibility that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Previously this antibody was reported to react with intestinal T-cell malignant lymphomas but not with peripheral tumours, or any B-cell lymphomas. We investigated 181 patients with malignant lymphomas and found that 19 out of 113 ATLLs were positive for HML-1. T-cell malignant lymphomas excluding ATLL also reacted with HML-1 (7/24), but all the B-cell lymphomas 0/33) and non-neoplastic lymph node and skin lesions (0/10) were negative for HML-1. In patients with ATLL and other T-cell malignant lymphomas, the positivity level of HML-1 was relatively higher in stomach (3/7) and tonsil (2/6) than that in lymph nodes (15/100) and skin (8/47). We observed one HML-1 positive ATLL patient with tumour formation in the skin and lymphadenopathy and marked infiltration of the large intestine but minimal involvement of other organs. Although HML-1 was frequently expressed in gastric infiltration of ATLL, the level of positivity was too low in lymph nodes to support the hypothesis that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Some of the HML-1 positive ATLL cases co-expressed CD30. Furthermore, three of six cases of Ki-1 lymphoma (large anaplastic cell lymphoma) were positive for HML-1. We conclude that expression of HML-1 in ATLL reflects an activated state of the lymphoma cells, but not the intestinal origin of ATLL cells.     

Precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma and acute biphenotypic leukemias

Session 4 of the 2005 Society of Hematopathology/European Association for Haematopathology Workshop focused on case presentations of precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (pre-T ALL/LBL) and acute biphenotypic leukemia. Pre-T ALL represents approximately 15% of childhood and 25% of adult ALL cases. Pre-T LBL comprises 85% to 90% of LBL and frequently manifests as a mediastinal mass. Gene expression studies have shown distinct subtypes of LYL1+, HOX11+, TAL1+, and MLL+ pre-T ALL/LBL. HOX11 overexpression may correlate with a good prognosis in adult pre-T ALL. ABL gene amplification and NOTCH1 gene mutations in subsets of pre-T ALL/LBL suggest patients may benefit from therapy with tyrosine kinase and gamma-secretase inhibitors, respectively. Acute biphenotypic leukemias are characterized by a single population of blasts that express myeloid, T- or B-lineage antigens in various combinations and account for fewer than 4% of all acute leukemias. The blasts have a high incidence of chromosome abnormalities. An accurate diagnosis of pre-T ALL/LBL and acute biphenotypic leukemia requires a multiparametric approach, including examination of morphologic features, immunophenotype, clinical characteristics, and cytogenetic and molecular findings.     

Gene rearrangements in T-cell lymphoblastic lymphoma

This study presents an examination of the Ig heavy chain (IgH) and T-cell receptor gamma (TCRγ) genes in a series of 39 CD3-positive T-cell acute lymphoblastic leukaemia (ALL) cases with and without co-expression of CD79a; 30/39 cases had a rearrangement of the TCRγ genes and two of these 30 cases also demonstrated an IgH rearrangement. No cases had solely an IgH rearrangement. The conclusion of the study is that lymphoblastic lymphoma cases that are positive for CD3 are of T-cell lineage, regardless of CD79a expression. Copyright © 1999 John Wiley & Sons, Ltd.     

T-cell lymphoblastic leukemia/lymphoma presenting in a recurrent thymoma

A lymphoblastic malignancy presented as the lymphoid component of a recurrent invasive lymphocyte-rich thymoma that had been previously resected and treated with chemotherapy. This high grade lymphoid neoplasm concurrently involved mediastinal nodes and subsequently disseminated to pleural fluid and peripheral blood. Lymphocytes with convoluted nuclei demonstrated a T-lymphoblastic phenotype (UCHL1+, Leu-22+, TdT+) by immunohistochemical studies. T-cell lymphoblastic leukemia/lymphomas in this clinical setting have not been reported, and this case suggests that neoplastic transformation of lymphocytes may occur in longstanding refractory thymomas.     

5 Year old girl with malignant lymphoblastic lymphoma: challenges of managing haematological malignancies in a developing country

Background

Lymphoblastic lymphoma (LBL) is a neoplasm of lymphoblasts. The condition is predominantly lymph node-based disease arising from immature T cells in 85–90% of cases and immature B cells in the remainder. The lymphoma is aggressive, progresses rapidly, and often presenting as stage IV disease in more than 70% of patients. This disease makes up approximately 20% of childhood NHL

Objective

To show case the management of childhood lymphoblastic lymphoma and the handicap faced by the oncologists and pathologists.

Methods

A review of the index case was carried out at the paediatric department of Federal Medical Centre, Bida, Nigeria. This review took into cognisance patient''s demographic bio data, case history, general and physical examination, various investigations, methods of diagnosis and the type treatment. A comprehensive analysis and account of events before and after the commencement of chemotherapy were also reviewed.

Results

This case identifies a 5 year old girl with aggressive malignant lymphoma; lymphoblastic type and the myriad of limitations faced by oncologists and pathologists in the management of haematological malignancies. Socio-cultural, financial (cost implications for the patient for both investigative and therapeutic interventions), inadequate resources and facilities were identified as some of the constraints leading to inadequate management and poor outcome in patients with this condition.

Conclusion

Given the limitations associated with the management of cancers in this part of the world, efforts on the part of government and non-governmental agencies are necessary to strengthen and upgrade the existing facilities in various hospitals. The social welfare departments of tertiary hospitals should be adequately funded to meet the demand of this group of patients.     

Development-dependent expression of cyclin D3 in precursor T-cell lymphoblastic leukemia/lymphoma

In contrast to the clear oncogenic role of cyclins D1 and D2, cyclin D3 is suggested to have a role in the initiation and/or maintenance of differentiation in a lineage-associated manner in addition to its basic role in proliferation. Recently, it has been reported that in cyclin D3-deficient mice, normal expansion of T lymphocytes is impaired because of maturation arrest at the double-negative thymocyte stage, suggesting a crucial role for cyclin D3 in early T-cell development. Therefore, cyclin D3 expression was examined in 36 human precursor T-lymphoblastic leukemia/lymphomas (T-LBLL), a neoplastic counterpart of T cells at the early developmental stages of differentiation. Using a standard panel of differentiation markers, all T-LBLL were categorized into four stages according to differentiation: progenitor, double-negative, double-positive, and single-positive stages. Cyclin D3 expression was initiated at the boundary between double-negative and double-positive stages, and was sustained in the single-positive stage. T-cell receptor was expressed simultaneously with cyclin D3, whereas CD79a expression was specific in the double-negative stage, and thus it was inversely correlated with that of cyclin D3. Taken together with the crucial and non-redundant role in T-cell development in mice, this molecule is suggested to play an important role in human T-cell development.     

Treatment of adult T-cell leukaemia/lymphoma: current strategy and future perspectives

Human T-cell leukaemia virus type I (HTLV-I) associated adult T-cell leukaemia/lymphoma (ATL) carries a very poor prognosis due to an intrinsic resistance of leukaemic cells to conventional or even high doses of chemotherapy and to an associated severe immunosuppression. Therefore, the potential role of conventional chemotherapy, high dose chemotherapy with autologous or allogeneic bone marrow transplantation remains to be defined. Important progress was achieved in the treatment of ATL with the combination of zidovudine (AZT) and interferon-alpha (IFN) which produces a high response rate in ATL patients with minimal side effects. This treatment seems to prolong the survival of patients much more than intensive chemotherapy. The success of this potentially anti-retroviral approach in the treatment of ATL suggests the existence of continuous HTLV-I replication in vivo. These encouraging results may be improved by the use of higher doses of AZT and IFN combined with other anti-retroviral agents. However, since cure seems still elusive, new therapeutic approaches or new combinations are required. For example, biological mediators such as retinoid acid, which induces apoptosis of ATL cells in vitro, may reduce drug resistance and stimulates immunity to restore anti-tumour activity against ATL cells. Alternatively, immunotherapy with anti-interleukin-2 receptor monoclonal antibodies or injection of cytotoxic T-cells directed against virus antigens could be interesting approaches which may merit further investigations in the near future. Finally, the recent demonstration that the combination of arsenic trioxide (As) and IFN induces a specific degradation of the viral transactivator Tax followed by cell cycle arrest and apoptosis of HTLV-I positive cells may constitute a valuable addition to ATL treatment.     

The histopathology of adult T-cell lymphoma/leukaemia in blacks from the Caribbean

The histopathological features of seven cases of adult T-cell lymphoma/leukaemia (ATLL), all occurring in black patients from the Caribbean, are described. Lymph node infiltrates are initially restricted to the paracortical zone, with preservation of the nodal shape and subcapsular sinus, and accompanied by a proliferation of post-capillary venules. Cytologically, a range of cell types is present, from smaller cells with irregularly shaped nuclei and clumped nuclear chromatin to larger cells with dispersed chromatin and more prominent nucleoli, apparently corresponding to the stages of peripheral T-lymphocyte transformation. The proportion of each cell type present varies from case to case, as do the numbers of admixed eosinophils, plasma cells and interdigitating reticulum cells. These histological appearances are very similar to those of the pleomorphic T-cell lymphoma described in Japan, which also shows many clinical similarities, including a high incidence of complicating hypercalcaemia. There is a strong association in both Japanese and Caribbean patients with a recently described human retrovirus, HTLV, which occurs endemically in those areas where the disease clusters. Morphological similarities exist between ATLL and other peripheral T-cell lymphomata and leukaemias. These are illustrated by one notable 'linking' case. However, while related to other disorders of mature T-lymphocytes, ATLL nevertheless represents an identifiably separate clinicopathological entity.     

Cellular therapy to treat haematological and other malignancies: progress and pitfalls

The recent Food and Drug Administration (FDA) approval of a cellular therapy to treat castration resistant prostate cancer has reinforced the potential of cellular therapy to consolidate current pharmacological approaches to treating cancer. The emergence of the cell manufacturing facility to facilitate clinical translation of these new methodologies allows greater access to these novel therapies. Here we review different strategies currently being explored to treat haematological malignancies with a focus on adoptive allogeneic or autologous transfer of antigen specific T cells, NK cells or dendritic cells. These approaches all aim to generate immunological responses against overexpressed tissue antigens, mismatched minor histocompatability antigens or tumour associated antigens. Current successes and limitations of these different approaches will be discussed with an emphasis on challenges encountered in generating long term engraftment, antigen selection and implementation as well as therapeutic immune monitoring of clinical responses, with examples from recent clinical trials.     

Flow cytometry in the differential diagnosis of lymphocyte-rich thymoma from precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma

We compared the antigen expression profile of thymocytes in lymphocyte-rich thymoma with that of precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-cell ALL/LBL) cells using 4-colorflow cytometry. In all 15 thymoma cases, the thymocytes demonstrated 3 distinct subpopulations. The least mature cells (double-negative) expressed low-density CD2 and CD5, high-density CD7, CD10, CD34, and heterogeneous CD4 and CD8. They had the lowest density CD45 expression and were surface CD3-. The immature cells (double-positive) expressed CD2, CD5, CD7, CD4, CD8, heterogeneous surface CD3, and intermediate-density CD45. They were CD10- and CD34-. The mature cells (single-positive) expressed CD2, surface CD3, CD5, CD7, and CD4 or CD8. The heterogeneous expression of surface CD3, CD4, and CD8 also created a characteristic smearing pattern for these antigens. In all 15 T-cell ALL/LBL cases, the lymphoblasts formed a tight cluster without discrete subpopulations or smearing pattern. Of 5 double-negative cases, 4 demonstrated loss of CD2, CD10, or CD34 expression. Of 7 double-positive cases, 5 showed complete loss of surface CD3, CD2, and/or CD5; 4 were CD10+; and 2 were CD34+. Of 3 single-positive cases, 2 showed loss of CD2 and/or aberrant expression of CD34. Analysis of antigen expression pattern, the presence or absence of T cell-associated antigen deletion, and the expression of CD10 and CD34 by 4-color flow cytometry can help differentiate thymoma from T-cell ALL/LBL.     

Viruses and lymphoma/leukaemia

Viruses of the retrovirus and herpesvirus families are aetiological agents of human leukaemias and lymphomas. The human T-cell leukaemia virus type 1 causes adult T-cell leukaemia and the Epstein-Barr virus is associated with Burkitt's lymphoma, lymphomas in immunosuppressed people, and Hodgkin lymphoma. The discovery of human herpesvirus type 8 has led to the identification of a rare and unusual group of virus-associated lymphoproliferative diseases. Individuals infected with the human immunodeficiency virus are at greatly increased risk of developing lymphoma but here the mechanism of lymphomagenesis is indirect. Recent data suggest that hepatitis C virus infection is also associated with an increased incidence of lymphoma, whereas data relating to SV40 remain controversial.     

Expression of human T-cell leukaemia virus type I and associated antigens,and interleukin-2 and receptor in lymph nodes of adult T-cell leukaemia/lymphoma

To examine the relationship between the expression of human T-cell leukaemia virus type (HTLV-I) mRNA and associated antigens and clinicopathological features, we studied 31 lymph nodes of patients with adult T-cell leukaemia/lymphoma (ATLL) and related diseases, using in situ hybridization and immunohistochemistry. We classified the patients into four types on the basis of their clinicopathological features (HTLV-I associated lymphadenitis, incipient ATLL, ATLL with complete HTLV-I provirus, and ATLL with defective HTLV-I provirus. The expression of HTLV-I mRNA was detected in all 3 patients with incipient ATLL, in 5 of 10 patients with defective-provirus ATLL, in 5 of 11 patients with complete-provirus ATLL, and 3 of 7 with HTLV-I associated lymphadenitis, but the amounts were very small; approximately 1 in 10000–200000 lymph node cells express the viral genomes. This suggests that expression of viral genomes may not be important for immortalization, but it is important that to note the capacity for HTLV-I infection is preserved in each group of non-neoplastic and neoplastic states. HTLV-I mRNA was detected only in lymphocytes and/or lymphoma cells, but the HTLV-I associated antigens (env, gag and pX) were found in histiocytes and endothelial cells, as well as in lymphocytes and/or lymphoma cells. Anti-interleukin 2 receptor (IL-2R) antibody reacted with the giant cells of incipient ATLL and with the transformed lymphocytes and immunoblast-like cells of the HTLV-I-associated lymphadenitis but not with the lymphocytes in the background. Of the typical ATLL, IL-2R was found in both lymphoma cells and giant cells. IL-2 was rarely detected.     

Febrile neutropenia in haematological malignancies

Fever is the principle sign of infection in neutropenic patient and frequently may be the only evidence of infection. The pattern of fever in neutropenia is non-specific and not pathognomonic of any type of infections or non-infectious process and can be suppressed by the antipyretic effects of drugs such as corticosteroids. Neutropenia, resulting from cytotoxic chemotherapy is the most common risk factor for severe infections in hematological malignancies. The duration of neutropenia also contributes significantly to the risk of serious infections. This risk is significantly greater a lower neutrophil counts, such that 100% patients with ANC <100 cells/microl lasting 3 weeks or more develop documented infections. The prompt initiation of empirical antibiotics in febrile neutropenia has been the most important advance in the management of the immunocompromised host. The initial empirical antibiotic regimen started at presentation of the febrile episode frequently requires modifications especially in high-risk febrile neutropenia. Neutropenic patients who remain febrile despite 4-7 days of broad spectrum antibacterial therapy are at a high risk of invasive fungal infection. Empirical antifungal therapy with Amphotericin B in persistently febrile neutropenic patients and other high risk patients has shown to reduce the risk of invasive fungal infection by 50-80% and the risk of fungal infection related mortality by 23-45% in 1980's. The IDSA has recommended that amphotericin B at 0.5-0.7 mg/kg/day be administered till marrow recovery. This approach is limited however by the adverse effects caused by drug infusion (fever, chills, myalgias, nausea, hypotension and bronchospasm). Lipid formulations which improve the therapeutic ratio of the traditional formulation are available. The safety and efficacy of these formulations is well established. These formulations have comparable efficacy and are less nephrotoxic than conventional amphotericin B.A lipid formulation of amphotericin B is appropriate as initial empirical therapy or as definitive therapy for proven mycosis in high risk patients receiving concomitant nephrotoxic drugs (cyclosporine), those with pre-existing renal impairment and those with protracted neutropenia during which dose limiting toxicity may occur.