The Differences between Lymphoma and Leukemia Type of Adult T-cell Leukemia

The difference between lymphoma type and leukemia type of adult T-cell leukemia (ATL) were analysed with 102 Japanese patients all positive for human T-cell leukemia virus type I (HTLV-I) antibody. They were classified into three groups on findings at first medical examination: lymphoma type cases, leukemia type cases, and mixed type (leukemia type plus lymphadeno-pathy) cases. Lymphoma type patients had several or more enlarged lymph nodes the largest of which was greater than 1 cm in diameter and with practically no abnormal lymphocytes (ATL. cells), which are characteristic of ATL, in the peripheral blood. Leukemia type patients had 10% or more ATL cells in the peripheral blood and had no detectablle lymphadenopathy Lymphoma type patients often complained of detectable lymphadenopathy, while leukemia type patients complained frequently of general fatigue and skin eruption. Mixed type patients more frequently had signs and symptoms which were characteristic of both types: lymphadenopathy and 10% or more ATL cells in the peripheral blood. Mixed type: ATL had a poorer prognosis than either lymphoma type or leukemia type. The median survival time was 3 months for mixed type patients, 10.5 months for lymphoma type patients, and 13.5 months for leukemia type patients. Complications and causes of death have also been touched upon. Clinicians are thus advised to consider ATL patients separately according to their clinical manifestations.     

Comparison of CHOP versus VEPA Therapy in Patients with Lymphoma Type of Adult T-cell Leukemia

Forty-six Japanese patients with lymphoma type of adult T-cell leukemia (ATL) were treated with one of the 4-drug combinations, CHOP or VEPA regimen. Fourteen patients were treated with CHOP, while 32 were treated with VEPA. The complete response i(CR) rate and the 5-year survival rate of patients treated with CHOP were 35.7% and 7.1%, respectively, while for those treated with VEPA the rates were 43.8% and 18.7%, respectively. Only two patients treated with CHOP survived for more than 1 year, while the others died within 1 year. On the other hand, 13 patients treated with VEPA survived for more than 1 year. The 32 VEF'A-treated patients were divided into two groups according to the duration of survival: (A) 13 surviving for more than 1 year, and (B) 19 surviving for less than 1 year. They were compared for pretreatment characteristics. The differences between the two groups related to hepatomegaly, the presence of B symptoms, lactic dehydrogenase (LDH) and calcium levels. The results indicate that these factors are important in predicting the response and survival of patients with lymphoma type of ATL.     

Clinicopathological Features of Adult T-Cell Leukemia with CD30 Antigen Expression

Recently, several cases of adult T-cell leukemia (ATL) with CD30 antigen have been reported, but its clinical significance remains unknown. Accordingly, we studied CD30 antigen expression in ATL cases and documented the clinicopathological characteristics of these cases.

Immunohistochemical and clinical characteristics were studied in 46 patients with malignant lymphoma or benign lesions of lymphoid tissue, who had antibodies against human T-cell leukemia virus type I (HTLV-I). Monoclonal integration of HTLV-I provirus was demonstrated in the tumor cells in 36 (ATL) of the 46 cases. CD30 antigen expression was evident in seven of these 36 cases (19.4%), however it was not seen in any of the ten cases lacking the integration of HTLV-I provirus. A comparison of ATL cases with and without CD30 antigen expression revealed significantly larger numbers of abnormal lymphocytes in the peripheral blood and lower serum calcium levels in ATL expressing CD30 antigen.     

Unusual Morphological Features of Adult T-cell Leukemia Cells with Aberrant Immunophenotype

We describe 4 cases of adult T-cell leukemia (ATL) with unusual morphology and aberrant immunophenotype. All patients were Japanese and born in the Nagasaki district, an area endemic for HTLV-I. Peripheral blood and/or bone marrow films revealed bizarre giant cells with and without large nucleoli; the cells were 5 to 6 times the diameter of erythrocytes, resembling Hodgkin's cells. Some peripheral blood cells were morphologically similar to prototypic ATL cells, while many other cells in the bone marrow showed unusual morphology. Furthermore, leukemic cells had aberrant immunophenotypes such as the CD8-positive type in patients 1 and 2, the CD4^- ˙ CD8^- double-negative type in patient 3, and the CD5 antigen defect in patient 4. All patients had marked elevations of the serum calcium and LDH and organomegaly, while all had a short survival. Anti-HTLV-I antibodies and provirus DNA monoclonality were demonstrated in all patients.

The results suggested that the unusual morphology and aberrant ATL cell immunophenotype may be indicative of a high grade malignant behaviour of ATL.     

Adult T-Cell Leukemia/Lymphoma and Cluster of HTLV-I Associated Diseases in Brazilian Settings

We studied the transmission routes of human T-cell lymphotropic virus type I (HTLV-I) within families of 82 Brazilian patients diagnosed with adult T-cell leukaemia/lymphoma (ATL). Diagnosis of ATL in 43 male and 39 female patients was based on clinical and laboratory criteria of T-cell malignancy and detection of HTLV-I monoclonal integration. Samples were tested for HTLV antibodies and infection was confirmed as HTLV-I by Western Blot and/or polymerase chain reaction (PCR) assays. Overall 26/37 (70%) of mothers, 24/37 (65%) of wives, 8/22 (36%) of husbands, 34/112 (30%) of siblings and 10/82 (12%) offspring were HTLV-I infected. In 11 ATL patients, mothers were repeatedly HTLV-I seronegative, but HTLV-I pol or tax sequences were detected in 2 out of 6 cases tested by PCR. ATL patients with seronegative mothers related the following risk factors for HTLV-I infection: 6 were breast-fed by surrogate mothers with unknown HTLV-I status, 4 had a sexually promiscuous behaviour and 1 had multiple blood transfusions at a young age. Familial aggregation of ATL and other HTLV-I associated diseases such as HTLV-I myelopathy (HAM/TSP) and or uveitis, ATL in sibling pairs or in multiple generations was seen in 9 families. There were 6 families with ATL and TSP sibling pairs. In 3 families at least one parent had died with lymphoma or presenting neurological diseases and 2 offspring with ATL. Further to the extent of vertical and horizontal transmission of HTLV-I infection within ATL families, our results demonstrate that mothers who provide surrogate breast-milk appear to be an important source of HTLV-I transmission and ATL development in Brazil.     

Survey of Anti-human T-Cell Leukemia Virus Type I Antibody in Family Members of Patients with Adult T-Cell Leukemia

To evaluate the intrafamilial clustering of HTLV-I, we examined the sera or plasma of 296 healthy family members of patients with adult T-cell leukemia (ATL) for anti-HTLV-I antibodies. Of 296 subjects, 132 (44.6%) had anti-HTLV-I antibodies. Fifty-nine (41.0%) out of 144 males and 73 (48.0%) out of 152 females were seropositive. The positive rates of antibody to HTLV-I increased with age, especially between the 30–39 and the 40–49 age groups. Five out of 6 fathers, 3 out of 4 mothers, 31 (60.8%) out of 51 spouses, 40 (63.5%) out of 63 siblings and 46 (33.8%) out of 136 children of patients with ATL had anti-HTLV-I antibodies. Of 74 children with an ATL father, 14 (18.9%) were seropositive, while 32 (51.6%) out ot 63 children with an ATL mother were seropositive. This difference was statistically significant ( P <0.001). Of those children with an ATL father, 12 (26.1%) out of 46 whose mothers were HTLV-I carriers had antibodies to HTLV-I. In contrast, none of the 13 children whose mothers were not carriers were seropositive. These results supported the hypothesis that the mother-to-child transmission is one of the most important modes of HTLV-I transmission. In wives of male patients with ATL, the positive rate of antibody to HTLV-I was 65.6% (21/32), and in husbands of female patients, it was 52.6% (10/19). The high positive rate of antibody to HTLV-I not only in wives of male patients but also in husbands of female patients suggests that either HTLV-I is more frequently transmitted from wives to their husbands than we had originally expected, or that ATL may develop even in wives who acquire HTLV-I from their husbands after marriage.     

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.     

Novel Interleukin-2 Dependent T-Cell Line Derived from Adult T-Cell Leukemia Not Associated with Human T-Cell Leukemia Virus Type I

A novel interleukin-2 (IL-2)-dependent T-cell line, WHN2, was established from a patient with adult T-cell leukemia (ATL) not associated with human T-cell leukemia virus type I (HTLV-I). Neither the original leukemic cells nor the WHN2 cells showed proviral integration in their cellular DNAs by Southern blot analysis. The surface phenotype showed that both the original leukemic cells and the WHN2 cells had a common phenotype of ATL, i.e., positive for CD2, CD4, human leukocyte antigen DR (HLA-DR) and CD25, but negative for CD8, a characteristic of helper/inducer T-cells. Most of the chromosomal abnormalities of the original leukemic cells were maintained in the WHN2 cell line. Furthermore, Southern blot analysis of the T-cell receptor β -chain gene rearrangement revealed that the original leukemic cells and WHN2 cell line had identical patterns, suggesting that the WHN2 cell line was truly derived from the original leukemic cells. Dose-dependent growth on IL-2 was demonstrated, and at the maximal stimulation, the number of cells doubled within three days. This IL-2-dependent growth was inhibited by the simultaneous existence of anti-IL-2 receptor a and β chain antibodies. These results indicate that the character of the WHN2 cell line is similar to that of the cell lines derived from ATL associated with HTLV-I. Thus, the HTLV-I-negative ATL cell line, WHN2, should be useful in the comparative study of the pathogenesis of ATL associated with or without HTLV-I.     

Plasma Soluble CD30 as a Possible Marker of Adult T-cell Leukemia in HTLV-1 Carriers: a Nested Case-Control Study

Elevated levels of soluble CD30 (sCD30) are linked with various T-cell neoplasms. However, the relationship between sCD30 levels and the development of adult T-cell leukemia (ATL) in human T-cell leukemia virus type 1 (HTLV-1) carriers remains to be clarified. We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers. We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sCD30 concentration at baseline was significantly higher in cases than in controls (median 65.8, range 27.2-134.5 U/mL vs. median 22.2, range 8.4-63.1 U/mL, P=0.001). In the univariate logistic regression analysis, a higher sCD30 (≥30.2 U/mL) was significantly associated with ATL development (odds ratio 7.88 and the 95% confidence intervals 1.35–45.8, P = 0.02). Among cases, sCD30 concentration tended to increase at the time of diagnosis of aggressive-type ATL, but the concentration was stable in those developing the smoldering-type. This suggests that sCD30 may serve as a predictive marker for the onset of aggressive-type ATL in HTLV-1 carriers.     

IgG-κ-Type Plasmacytoma Secreting Salivary-Type Amylase in Adult T-Cell Leukemia

A IgG-κ-type plasmacytoma secreting salivary-type amylase ectopically is reported in a patient with smouldering adult T-cell leukemia(ATL). The patient had plasmacytomas in the distal region of the right femur, the proximal region of left tibia, and the left paranasal sinus. Both his serum and urine contained high levels of amylase. The presence of IgG-κ and S-type amylase in the plasmacytoma cells was confirmed immunocytochemically. In addition, he was also positive for the antibody against the human T-cell leukemia virus type I (HTLV-I), and had abnormal lymphocytes with convoluted nuclei(ATL cells) in the peripheral blood. The monoclonal integration of HTLV-I proviral DNA was demonstrated in the leukemic cells of the peripheral blood, but not in the plasmacytoma cells. Our case suggested that not only can HTLV-I infection play a role in the development of ATL, but may also induce a B-cell malignancy in an indirect manner, and even an ectopic amylase producing plasmacytoma.     

A Case of Adult T-Cell Leukemia Initiated with Central Nervous System Symptoms

We treated a 52-year-old Japanese woman with adult T-cell leukemia(ATL) initiated with central nervous system (CNS) symptoms.Her chief complaints were paraplegia and left facial palsy.CNS-ATL was diagnosed because of the following three features.1) Various sized lymphoid cells with marked nuclear convolutionwere numerous in her cerebrospinal fluid. 2) These cells werea monoclonal proliferation of T lymphocytes with OKT 4 marker.3) The patient's serum was positive for anti-ATL associatedantigen (ATLA). Although the neurological signs and symptomsimproved markedly after intrathecal administration of combinedchemotherapy (methotrexate, cytarabine and corti-costeroid),these ATL cells were highly resistant to radiation therapy.The abdominal mass which developed in the course of the diseasewas diagnosed as a tumor formed of ATL cells, and VEPA (vincristine,endoxan, prednisolone and adriamycin) was administered withmarked success.     

Electron Microscopic Study of Cell Lines Established from Adult T-Cell Leukemia--Coexistence of Adult T-Cell Leukemia Virus and Epstein-Barr Virus

Six cell lines established from five patients with adult T-cellleukemia (ATL) were studied by electron microscopy. From onepatient two cell lines were established, an interleukin 2-dependentline and a nondependent line. The interleukin 2-dependent T-cellline had only ATL virus (ATLV) particles. The interleukin 2-nondependentB-cell line had both ATLV particles and Epstein-Barr virus (EBV)particles. In two other B-cell lines and one undetermined cellline, both ATLV particles and EBV particies were seen. In oneB-cell line only a few EBV particles were seen. These findingssuggest that (I) interleukin 2 is necessary for the growth ofleukemic T-cells from ATL tissue samples, and (2) ATLV can infectnot only T-cells but also B-cells.     

Retrovirus-associated adult T-cell leukemia-lymphoma: an epidemiologic study of five cases among Hawaii-born offspring of migrant Japanese

Adult T-cell leukemia-lymphoma (ATLL) is a distinct clinicopathologic entity etiologically linked to HTLV-I infection. We have identified five cases of retrovirus-associated ATLL among Hawaii-born first generation offspring (nisei) of migrant Japanese. Four patients were offspring of migrant Japanese (issei) who emigrated to Hawaii from Okinawa, an HTLV-I endemic area. The fifth patient was born of parents who emigrated to Hawaii from Fukushima and Miyagi prefectures, HTLV-I nonendemic areas. Epidemiologic implications and family studies with regard to HTLV-I antibody testing of the index cases are discussed. The high rate of HTLV-I antibody seropositivity among family members and relatives indicates that the risk of acquiring HTLV-I infection and of developing ATLL persists long after migration. Documentation of ATLL among offspring of Japanese immigrants to Hawaii is an important observation because it confirms the potential for long latency between putative exposure to virus and the development of overt disease. Changing marriage patterns among the Hawaii-Japanese may weaken the risk of vertical virus transmission to the descendents of migrants from southern Japan, while increasing the risk to children born of mixed marriages. In addition, blood products derived from high-risk donors will constitute a continuing hazard if they are not subject to screening.     

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.     

Adult T-cell Leukemia/Lymphoma with a Giant Gastric Tumor: A Case Report

A rare case of adult T-cell leukemia/lymphoma with a giant exophyticgastric tumor invading the anterior abdominal wall is presented.The patient was a 52-year-old woman, who had a history of strongyloidiasis.Although the patient was serologically positive for HTLV-I antibody,there were no lymphoma cells in the peripheral blood or systemiclymphadenopathy. After two cycles of combination chemotherapy,the tumor was surgically resected. The pathological diagnosisof the resected specimen was T-cell lymphoma of the diffusemixed cell type. Flow-cytometric analysis of the lymphoma showeda CD4⁺and CD8⁺ phenotype. One month after surgery, the patientdeveloped hypercalcemia, resulting in acute renal and respiratoryfailure, and died. The prognosis of lymphoma-type ATL is knownto be extremely poor, and thus we should bear in mind that ATLcan take the form of a primary gastric mass without leukemicmanifestations.     

Efficacy and Safety of the Modified EPOCH Regimen (Etoposide,Vincristine, Doxorubicin,Carboplatin, and Prednisolone) for Adult T-cell Leukemia/Lymphoma: A Multicenter Retrospective Study

BackgroundWe retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen.Patients and MethodsPatients received up to 6 mEPOCH cycles. Etoposide (50 mg/m²/day), doxorubicin (10 mg/m²/day), and vincristine (0.4 mg/m²/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m²/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert’s formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6.ResultsIn 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation.ConclusionThe mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.     

HTLV-I infection of T and B cells of a patient with adult T-cell leukemia-lymphoma (ATLL) and transmission of HTLV-I from B cells to normal T cells

We analysed the DNA of different tissues of a patient (HS) with adult T-cell leukemia/lymphoma virus (HTLV-I). We detected viral sequences in fresh specimens from spleen, thymus, liver, skin and peripheral blood neoplastic lymphocytes. The pattern of HTLV-I intergration is identical in the leukemic cells and in all other tissues analysed, but the signal intensity is strongest in the leukemic cells, indicating the source of HTLV-I proviral sequences was the leukemic T-cells which had infiltrated these tissues. In fact, the cultured skin fibroblasts of the patient did not contain HTLV-I sequence. However, cultured lymphocytes of this patient was consistently an immortalized B-cell line containing HTLV-I sequences in a manner indicative of a polyclonal infection. This cell line was also infected with the Epstein-Barr virus (EBV). In order to determine whether HTLV-I alone was sufficient for B-cell immortalization, we obtained single cell clones by limiting dilution. The DNA of all the cell clones that we analysed contained both the HTLV-I and EBV genomes, suggesting that immortalization of the B-cell was more likely due to the EBV rather than HTLV-I. Infectious HTLV-I viruses produced by the B-cell line still had the propensity to infect and transform T-lymphocytes in normal human umbilical cord blood. Unlike the parental B cells, the transformed T lymphocytes were clonally selected. Our results indicate that although the predominant infected cell population of the patient was his leukemic T lymphocytes, some of his EBV-positive B-lymphocytes were also polyclonally infected. The latter had a growth advantage in culture over the T lymphocytes but the virus produced by these immortalized B cells has not been adapted and has maintained its tropism for T cells.