Virus associated adult T-cell leukemia (ATL) in Japan: clinical, histological and immunological studies

Virus associated adult T-cell leukemia/lymphoma (ATLL), which includes both adult T-cell leukemia (ATL) and its non-leukemic counterpart (NLATL) was studied clinically, histologically, and immunologically. The disease usually occurred in the sixth decade in both sexes equally. The patients had a rapid clinical course with frequent leukemic changes, lymphadenopathy, hepatomegaly, and occasional skin rash. Bone marrow involvement with mild infiltration and hypercalcemia were more frequent in ATL than in NLATL. Histologically the disease was categorized as malignant lymphoma, diffuse pleomorphic type with cerebriform nuclear giant cells. The lymphoma was characterized by diffuse proliferation of tumor cells with irregular nuclear configurations, varying in size and shape, and the presence of giant cells with highly convoluted cerebriform nuclei. The giant cells seemed to be a diagnostic marker. Immunologically, the tumor cells usually possessed the surface antigens recognized by OKT 3, 4, Leu 8 and anti-Tac antibodies, indicating that they were lymphomas of helper/inducer peripheral T-cells with the receptor for interleukin 2, but they demonstrated no helper/inducer functions. The patients often died of opportunistic infections due to T-cell dysfunction caused by the disease itself and strong chemotherapy.     

Malignant lymphomas in Japan: Epidemiological analysis of adult T-cell leukemia/lymphoma (ATL)

The incidence of malignant lymphomas in Japan is relatively low compared to that in western European countries and the United States. However, in limited areas in Japan a specific type of lymphoid malignancy called adult T-cell leukemia/lymphoma (ATL), which is caused by human T-cell leukemia virus type I (HTLV-I), is highly prevalent, and there are also many healthy carriers of HTLV-I in the same areas. A cross-sectional seroepidemiological study of HTLV-I showed that the age-specific proportion of healthy HTLV-I carriers in these ATL-endemic areas increased with age, especially over 40, and was higher in females than in males. Three main routes of HTLV-I transmission are recognized: 1) vertical transmission from mother to child mainly through breast milk; 2) horizontal transmission from man to woman through semen, and; 3) parenteral transmission from carrier donor to non-carrier recipient. The annual incidence rate of ATL among HTLV-I carriers is estimated at 2.0 in males and 0.5 in females, and the cumulative risk for ATL in HTLV-I carriers during a 70-year life span is 1%–5%. Possible risk factors for ATL in addition to HTLV-I infection were considered, i.e. genetic factors, environmental factors, nutritional condition, thymus involution etc., but none of these were found to be clearly associated with ATL. To determine whether there exist particularly susceptible hosts for ATL in the ATL endemic areas, HLA types were examined, but no conclusive results on the positive relationships between HLA types and ATL manifestation or HTLV-I infection were obtained. From follow-up studies on the age-specific distribution of HTLV-I carriers in Japan, it is now speculated that the HTLV-I infection rate might have decreased naturally in the more recent generational cohort groups, even in the ATL-endemic areas. However, ATL in Japan is an important subject for study in the field of cancer epidemiology, and several trial intervention programs for the prevention of ATL, such as controls of vertical transmission from mother to child through breast milk, are now ongoing in the ATL-endemic areas of Japan.     

Malignant lymphomas in Japan: epidemiological analysis on adult T-cell leukemia/lymphoma

According to the Vital Statistics Japan Series in 1950-1981, the age-adjusted death rate for malignant lymphomas (ICDs, 200-202) in Japan has increased in recent years. A geographical clustering of malignant lymphomas in the Kyushu districts was observed both in the period 1969-1971 and more recently in 1979-1981. The excessive rate of malignant lymphomas in Kyushu was due to the high incidence of adult T-cell leukemia/lymphoma (ATLL). The distribution of healthy carriers of ATLV, a human retrovirus which is almost identical to HTLV, was closely related to that of patients with ATLL in Japan. Epidemiological features of the infectious mode of ATLV suggested two main routes of natural transmission, one from mother to child and the other from husband to wife. ATLV is considered to be a main causative agent of ATLL from virological and epidemiological evidence, but infection by this virus alone may not result in ATLL because the incidence of ATLL among ATLV carriers was apparently not very high even in endemic areas of ATLL. Thus, some risk factors other than ATLV, such as environmental and genetic factors, may contribute to the development of ATLL.     

Correlation of aberrant proliferation with T-cell growth factor in adult T-cell leukemia cells

Peripheral blood lymphocytes from seven patients with adult T-cell leukemia (ATL) were found to lack PHA-responsiveness. However, in most of the cases, minute but distinct proliferation could be induced and maintained by human spleen cell conditioned medium containing PHA or by a combination of PHA and conditioned medium of gibbon cell line, MLA-144 (MLA-144 CM). These results indicate that the lack of response to mitogens of ATL cells might be attributed not only to the failure of these cells to produce T-cell growth factor (TCGF) upon activation, but also to their poor responsiveness to TCGF. Furthermore, a direct proliferative response to mitogen-free MLA-144 CM was shown in two out of seven patients; these two patients experienced rapidly progressive clinical courses. This observation raises the possibility that TCGF promotes the growth of ATL cells in vivo, and is related to the clinical course of the disease.     

Urinary excretion of parathyroid hormone-related protein as a predictor of hypercalcemia in patients with adult T-cell leukemia.

Hypercalcemia with adult T-cell leukemia (ATL) is chiefly caused by an excessive production by tumor cells of parathyroid hormone-related protein (PTHrP). We have previously reported hypercalcemic patients with solid tumors to excrete a large amount of the C-terminal fragments of PTHrP (C-PTHrP) into their urine. To elucidate whether PTHrP production correlates with or predicts the development of hypercalcemia, we studied the urinary excretion of C-PTHrP in 36 ATL patients. The urinary excretion of C-PTHrP was in the normal range (< 0.40 nmol equivalent to PTHrP (109-141)/g creatinine) in HTLV-1-positive carriers (n 3), ATL patients in complete remission (n 2) and chronic type ATL patients (n 2). It was marginally increased in seven patients in partial remission, and gradually increased as the disease progressed. In 20 patients who died without or with hypercalcemia, it was increased to 1.98 +/- 0.69 (n 9) and 7.6 +/- 2.1 nmol/g creatinine (mean +/- SD, n 11, P < 0.01), respectively. Urinary C-PTHrP excretion was significantly correlated with serum calcium and LDH levels as well as with CD25-positive cells in the peripheral blood. In four patients whose urinary excretion had been serially determined, it increased prior to the development of hypercalcemia. The findings suggest the urinary excretion of C-PTHrP to be of use as a predictor of the development of hypercalcemia in ATL patients. In ATL patients whose urinary excretion of C-PTHrP is progressively increasing, the serum calcium concentration should be carefully monitored to prevent hypercalcemic crisis.     

成年人T细胞急性淋巴细胞白血病中Ikaros6表达及其临床意义

目的 检测成年T细胞急性淋巴细胞白血病（T-ALL）患者Ikaros6的表达,并探讨其临床意义.方法 提取成年T-ALL患者初发时骨髓单个核细胞的RNA,反转录为cDNA,采用反转录-聚合酶链反应（RT-PCR）扩增技术进行检测,测序进一步确定结果,并结合患者临床资料分析临床特点及其预后.结果 74例初发成年人T-ALL中,Ikaros6阳性率为21.6％（16例）,另外阳性患者较阴性患者更易发生髓外浸润（x2=4.084,P=0.043）,且外周血白细胞计数高（103.15×109/L比15.60×109/L）、贫血更严重（血红蛋白75.95 g/L比107.00 g/L）和血小板计数低（26.0×109/L比67.0×109/L）,但差异均无统计学意义（均P＞ 0.05）.Ikaros6阳性患者生存期短和具有高复发风险.结论 Ikaros6在成年人T-ALL中表达率较高,阳性患者具有外周血白细胞计数高和易出现髓外浸润等临床特点,预后差,具有高复发风险.Ikaros6可考虑作为成年人T-ALL分层治疗或预后判断的分子指标.     

Epstein-Barr virus-specific antibodies in patients with adult T-cell leukemia (ATL) and healthy ATL virus-carriers

Antibodies to Epstein-Barr virus (EBV)-capsid antigen (VCA), early antigen (EA) and EBV-associated nuclear antigen (EBNA) in the sera of 103 patients with adult T-cell leukemia (ATL) and the sera of 243 age- and sex-matched healthy adults, namely 99 anti-ATLA-positive (antibodies to ATL virus-associated antigen) and 144 anti-ATLA-negative individuals, were determined by indirect immunofluorescence. The anti-VCA titers in the sera from ATL patients were within the range observed in healthy controls. Anti-EA was found in 27% of the sera from ATL patients, but in only 8% of the sera from anti-ATLA-negative healthy controls. Antibodies to EBNA, which were present in almost all healthy adults, were not found in 30% of the sera from ATL patients. Of the sera of anti-ATLA-positive healthy adult donors 11% were negative for EBNA antibody. These results suggest that functional impairment of the T-cell system in most ATL patients, and also to a lesser extent in anti-ATLA-positive adults who might be healthy ATLV-carriers, may cause an unusual immune response of antibodies to EBV-associated antigens.     

Adenosine deaminase concentrations in leukaemia and lymphoma: Relation to cell phenotypes

Adenosine deaminase concentrations have been measured in the cells of 100 patients with acute leukaemia, 12 in blast transformation of chronic granulocytic leukaemia, 14 with chronic leukaemias and in 18 patients with lymphoma. The highest levels occurred in Thy-ALL (range 29.3–350, mean 109 units/10⁸ cells) but raised levels were also frequent in non-B, non-T ALL whether or not these were cALL antigen positive and raised levels also occurred in 50% of patients with AML. ADA concentrations were also moderately raised in the cells of 7 of 8 patients with T-CLL and T-prolymphocytic leukaemia whereas subnormal levels were found in B-CLL.Among the lymph node samples, the highest ADA levels occurred in diffuse undifferentiated and lymphoblastic types, shown to be of T-cell origin by immunological markers. The results confirm that ADA concentrations are generally higher in leukaemias of thymic or T-cell origin than in equivalent cases of B-cell or myeloid cell origin. The use of ADA inhibitors for treatment of Thy-ALL and chronic T-cell disorders is discussed.     

Clinical features of OKT4+/OKT8+ adult T-cell leukemia

Adult T-cell leukemia (ATL) has a range of clinical characteristics. Phenotypically the leukemic cells usually express the helper/inducer associated antigen OKT4 with lack of OKT8. We have observed three patients with acute ATL cytologically indistinguishable from OKT4+/OKT8- ATL but whose neoplastic cells had the unusual phenotype, OKT3+, OKT4+, OKT6-, OKT8+ OKT9+/-, OKT11+, Tac+/-, TdT-. All patients had abnormal karyotypes and antibodies against anti-ATL associated antigens as well as proviral DNA of human T-cell leukemia virus in the leukemic cells. The clinical course was complicated by skin eruptions, hypercalcemia, pulmonary infection and disseminated intravascular coagulopathy. All died of complications shortly after diagnosis. The clinical features of these patients were similar to those of OKT4+/OKT8- ATL. However, their acute course suggests that co-expression surface antigens OKT4 and OKT8 may be a sign of aggressive nature of the disease with poor prognosis.     

Adult T-cell leukemia cells expressing OKT 17 antigen in the activated state

The surface phenotype and the functional activities of leukemic cells from seven patients with adult T-cell leukemia (ATL) were studied using monoclonal antibodies OKT 3, 4 and 8, anti-Tac, and OKT 17. The latter defines the heterogeneity of the activated T4+ T cell subset. In all cases, ATL cells with the typical OKT3-T4+ T8- phenotype expressed OKT 17 antigen. In addition, in five out of the seven cases the fresh ATL cells possessed Tac antigen which is expressed on activated T cells in varying degree. After cultivation with PWM, most populations of ATL cells acquired Tac even in the cases expressing little antigen in uncultured preparations. However the PWM activated ATL cells did not lose OKT 17 antigen. Functional assays showed the suppressor activity of ATL cells on normal B cell differentiation in three out of six cases examined. These results suggest that ATL cells most probably arise from a particular subset characterized by OKT 17 antigen within the activated OKT4+ T cell subset.     

Dissociation of interleukin-2-mediated cell proliferation and interleukin-2 receptor upregulation in adult T-cell leukemia cells

We studied cell proliferation and interleukin-2 (IL-2) receptor upregulation mediated by exogenous IL-2 in leukemic cells from adult T-cell leukemia (ATL) patients to characterize some aspects of abnormal IL-2 receptor expression in ATL. Leukemic cells from 7 ATL patients examined showed no or very poor proliferative response to IL-2 though they expressed IL-2 receptors without any stimulation. In contrast, ATL leukemic cells cultured with IL-2 for 2 days expressed about twice as many IL-2 receptors as those of cells cultured without IL-2. Thus, in ATL leukemic cells, there seems to be a dissociation between the signal(s) for two different effects mediated by IL-2, cell proliferation and IL-2 receptor upregulation.     

Different prognostic factors for survival in acute and lymphomatous adult T-cell leukemia/lymphoma

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a clinically aggressive and heterogeneous entity; hence it is likely that different variants of ATLL have different prognostic factors. Methods: 95 patients with ATLL seen at our institution between 1987 and 2008 were included. Clinical data were compared, according to ATLL variant, using the Mann-Whitney and the Chi-square tests for continuous and categorical variables, respectively. Kaplan-Meier estimates compared using the log-rank test and Cox proportional-hazard test were used for the univariate and multivariate analysis, respectively. Results: Median age was 61 years with male-to-female ratio of 1.07:1. Patients with acute ATLL were more likely to present with bone marrow, liver and spleen involvement, higher β2-microglobulin and lower albumin levels. Poor performance status, high IPI score, presence of B symptoms, high LDH and low albumin levels were associated with a worse survival in lymphomatous ATLL. High LDH, high β2-microglobulin and high PIT score were associated with worse survival in acute ATLL. In the multivariate analysis, low albumin level and presence of B symptoms were independent factors for worse survival in lymphomatous ATLL, and high β2-microglobulin level was independent factor for worse survival in acute ATLL. Conclusions: Aggressive ATLL variants have a distinct, almost mutually exclusive profile of prognostic factors.     

Adenosine deaminase and purine nucleoside phosphorylase levels in acute myeloblastic leukemia cells. Relationship to diagnosis and clinical course.

The two enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), which are essential for normal lymphocyte function, have been investigated in leukemia.The enzyme activities have been measured in leukemia cells from 20 patients with AML, 19 patients with other leukemias and in leukocytes from 63 normal persons. It was found that the ADA activity in AML cells was above the normal range (P<0.01), with a correlation between peripheral blast percentage and ADA level (P<0.02). There was a slight relationship between the clinical course and survival time, response to chemotherapy (P<0.1) and survival time (P > 0.1), and ADA activity. Variable but also abnormal activities were found in other leukemias. The significance of increased ADA levels is discussed.The levels of PNP, which has not been determined before in AML in relation to ADA, showed remarkably constant levels. The levels in AML and the other groups analysed were essentially the same as those found in normal leukocytes.     

IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with an extremely poor prognosis. Maintaining ATLL cells in vitro is difficult and little is known about how they maintain themselves or grow in patients. Elucidating the interaction between ATLL cells and surrounding host factors might therefore provide important insights into pathophysiology. We cultured primary ATLL cells in various culture conditions using IL-2, IL-4 and feeder cells, and established two cell lines dependent on IL-2, IL-4 and a follicular dendritic cell-derived cell line, HK, in which OX40-ligand was induced. Our study indicates the importance of microenvironment in the homeostasis of ATLL.     

Clinical analysis of 33 patients with adult T-cell leukemia (ATL)-diagnostic criteria and significance of high- and low-risk ATL

The clinical characteristics of 33 patients with adult T-cell leukemia (ATL) are described. All patients were born and have lived in Miyazaki Prefecture (southwest of Japan). Because of a wide range of clinical presentations and courses, they were subdivided into 2 groups. In the high-risk group, patients presented with high white-cell counts (WBC greater than or equal to 20,000/microliter) and over 30% of abnormal lymphoid cells (18 patients) and hypercalcemia with a low percentage of leukemic cells (5 patients). In this group the median survival time was only 3 months despite various modes of treatment. In contrast, patients of the second group exhibited a low percentage of abnormal lymphoid cells (WBC less than 20,000/microliter and/or leukemic cells less than 30%) and had no hypercalcemia (8 patients). Their clinical course was chronic with a median survival of 8 months, regardless of modalities of treatment. Two patients went through a period when the number of circulating leukemic cells was low (less than or equal to 5%) before overt leukemia appeared. Other clinical features, signs, symptoms, routine laboratory data, serum anti-ATL-associated antibody, cell membrane markers and cytogenetic studies were similar to those observed in other districts of Kyushu island.     

成人早期前体T急性淋巴细胞白血病（ETP-ALL）与非ETP-ALL的临床特点对比

目的:对比分析成人早期前体T急性淋巴细胞白血病（ETP-ALL）与非早期前体T急性淋巴细胞白血病（non-ETP-ALL）的临床特点。方法:回顾性分析于我科系统诊治的成人T细胞急性淋巴细胞白血病（T-ALL）患者19例,其中ETP-ALL 6例,non-ETP-ALL 13例,对比两组患者临床基本状况、血液及骨髓检测结果、免疫分型结果及诱导治疗后缓解情况。结果:ETP-ALL组患者白细胞水平显著低于non-ETP-ALL组患者,血小板水平显著高于non-ETP-AL组患者,主要见于pro-T-ALL,首次诱导治疗后完全缓解或接近完全缓解（CR/CRi）率显著低于后者。结论:ETP-ALL患者具有较独特的临床特点,对常规诱导治疗反应差,有必要积极探索新的治疗方法和药物。     

Serum Soluble Interleukin-2 Receptor Levels in Patients with Adult T-cell Leukemia and Human T-cell Leukemia/Lymphoma Virus Type-I Seropositive Healthy Carriers

Using an enzyme-linked immunosorbent assay (ELISA) technique, we measured the soluble interleukin 2 receptor (s-IL-2R) levels in the sera of patients with adult T-cell leukemia (ATL) in Japan. The s-IL-2R levels in the sera of the ATL patients were markedly higher (range 540-310, 400 U/ml, mean ±SD=62,800 ±81,000 U/ml, n = 42) than those in normal individuals (range 42-950 U/ml, mean ±SD=322 ±198 U/ml, n = 35, P<0.01). The patients with acute-type or lymnhoma-type ATL had high s-IL-2R levels (range 11,900-310,400 U/ml, mean ±SD= 110,340 ± 370 U/ml, n = 15; range 26,400-214,400 U/ml, mean ±SD=90,170 ±59,040 U/ml, n = 7, respectively). All of the patients with hypercalcemia (Ca>10 mg/dl) or elevated serum LDH levels (LDH > 500 IU/liter) also had s-IL-2R levels above 10,000 U/ml. The high s-IL-2R levels in the sera of ATL patients indicate abnormal IL-2 receptor production and its release from the leukemic cells in vivo . Thus, the serum s-IL-2R level may be a sensitive and useful marker to monitor the total amount of tumor cells in ATL, especially in the lymphoma type. We next examined the serum s-IL-2R levels in human T-cell leukemia/lymphoma virus type-I (HTLV-I) seropositive healthy carriers to investigate whether there might he abnormal IL-2 receptor expression in such individuals. However, there was no statistically significant difference between the S-IL-2R level of 71 HTLV-I seropositive healthy carriers (range 65-880 U/ml, mean±SD =394±212 U/ml) and that of 71 age- and sex-matched normal individuals (range 33-950 U/ml, mean ±SD=357 ±224 U/ml) who lived in Okinawa Prefecture.     

Two cases of adult T-cell leukemia/lymphoma involving the terminal ileum

We describe two cases of adult T-cell leukemia/lymphoma (ATLL) with terminal ileal involvement. The first case, a 71-year-old man with lymphoma subtype of ATLL, had a polypoid lesion in the terminal ileum, in addition to a duodenal mass. The second case, a 58-year-old woman with lymphoma subtype of ATLL, had an irregular ulcerative lesion in the terminal ileum and multiple ulcers throughout the stomach. Biopsies from these lesions revealed mucosal invasion of ATLL cells in each case. In the second case, combination chemotherapy was transiently effective, resulting in the disappearance of gastric and terminal ileal lesions. Prospective and careful examination of additional cases should further characterize the clinicopathological features of terminal ileal involvement in ATLL.     

Genetic profile of adult T-cell leukemia/lymphoma in Okinawa: Association with prognosis,ethnicity, and HTLV-1 strains

Genetic alterations in adult T-cell leukemia/lymphoma (ATLL), a T-cell malignancy associated with HTLV-1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next-generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV-1 tax subgroup-A (HTLV-1-taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV-1-taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF-ĸB (eg, PRKCB, PLCG1, and CARD11) and T-cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome-associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV-1-taxB, HTLV-1-taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.     

Cardiac involvement with human T-cell lymphotrophic virus type-1-associated adult T-cell leukemia/lymphoma: The NIH experience

Malignant cardiac involvement is rare in patients with human T cell lymphotrophic virus type-1-associated adult T cell leukemia/lymphoma (ATLL). We report a single institution experience of eight patients with pathologically documented cardiac involvement with ATLL. Pericardial effusion and tamponade, cardiac valvular infiltration, valve leaflet tumor nodules and endocardial and myocardial tumors were observed. Cardiac involvement with ATLL was most often identified post-mortem; however, three cases were diagnosed clinically. All but one of the patients had the acute or lymphomatous subtypes of ATLL and had progressed through at least one prior systemic therapy. Patients with ATLL-related cardiac disease were also found to have pulmonary involvement suggesting that this may be a sign of increased risk of cardiac involvement. One patient with the chronic form of ATLL remains alive 10 years after undergoing cardiac valve replacement.