Clinicopathological studies of a patient with adult T-cell leukemia and pseudogynecomasty

We present a rare case of adult T cell leukemia/lymphoma (ATL) in which leukemic T cells expressed CD4 and CD25 surface antigens and infiltrated mammary glands during clinical course of the disease. A 40-year-old male was admitted with long-standing skin lesions and leukocytosis. Peripheral blood lymphocytes were highly pleomorphic and presented CD2, CD4, CD25, CD38 membrane surface antigens. The patient proved to be seropositive for human T-cell lymphotropic virus type I (HTLV-I) antibodies. Monoclonal expansion of lymphoid cells integrated with HTLV-I genome was observed, and the diagnosis of ATL chronic type was made. He underwent a chemotherapy regimen, and skin lesions and leukocytosis improved markedly. He progressed with an indolent clinical course of ATL, when he was admitted with bilateral hyperplasia of breast, recurrent skin lesions, and leukocytosis. Breast biopsy revealed bilateral gynecomasty, extensive leukemic infiltration of typical ATL cells in the mammary glands, and the presence of mammary epithelial cells productively infected with HTLV-I. This is the first report describing invasion of the mammary tissue with HTLV-I-transformed T-cells and HTLV-I-associated breast disease.     

Adult T-cell leukemia/lymphoma not associated with human T-cell leukemia virus type I.

We describe five patients with adult T-cell leukemia/lymphoma (ATL) with neither integration of human T-cell leukemia virus type I (HTLV-I) into their leukemia cells nor anti-HTLV-I antibody in their sera. These findings indicate that HTLV-I may not have been involved in leukemogenesis in these patients. The clinicohematological, cytopathological, and immunological features of HTLV-I-negative ATL were exactly the same as those of HTLV-I-associated ATL. Leukemia cells with pleomorphic nuclei, generalized lymphadenopathy, hepatosplenomegaly, skin lesions, hypercalcemia, and elevated lactate dehydrogenase levels, all of which are characteristic features of typical ATL, were also seen in these patients with HTLV-I-negative ATL. Leukemia cells expressed T3, T4, and pan-T-cell antigens in three cases, and T3 and pan-T-cell antigens in two. All five patients had lived in ATL-nonendemic areas. The finding of HTLV-I-negative ATL suggests that factor(s) other than HTLV-I infection may be involved in ATL leukemogenesis.     

Adult T-cell leukemia following long-term remission from non-Hodgkin's lymphoma

A female patient who had been initially diagnosed with non-Hodgkin's lymphoma (NHL) and achieved complete clinical remission with combined chemotherapy, developed overt adult T-cell leukemia (ATL) after 9 yr of disease-free survival. This is the first case of the development of ATL following the complete remission of NHL. Secondary malignant neoplasms are not well-documented in patients previously diagnosed with Hodgkin's disease. Although there have been a few reports concerning the occurrence of secondary malignancy in patients with non-Hodgkin's lymphoma (NHL), there has never been a documented case of ATL following long-term survival from NHL. Here, we report a case of typical adult T-cell leukemia (ATL) which occurred after 9 yr disease-free survival from NHL.     

IgA multiple myeloma coexistent with atypical adult T-cell leukemia

We report a 65-yr-old male with adult T-cell leukemia (ATL) who developed multiple myeloma (MM) concomitantly. Skin lesions and peripheral leukocytosis were noted during the 5-yr observation period. There was abnormal lymphocytosis with indented or lobulated nuclei in the peripheral blood and in the bone marrow. The neoplastic cells reacted with monoclonal antibodies, OKT3, OKT4, OKIa1 and anti-Tac. His serum was positive for the antibodies to ATL-associated antigens. Human T-cell leukemia virus (HTLV) proviral DNA was detected in the leukemic cells. Thus, a diagnosis of ATL was made. There was IgA (k) paraprotein in his serum, and Bence-Jones protein (k) in urine samples. Fine needle aspiration revealed pathologic flaming plasma cells. Multiple osteolytic lesions appeared on his skull 5 yr after the initial examination. Thus, a diagnosis of MM concomitant with ATL was made.     

Multiple myeloma superimposed on adult T cell lymphoma

A 77 year-old male was admitted to the hospital because of lumbago and M-proteinemia. IgA (kappa) monoclonal protein (8,100 mg/dl) was demonstrated in serum, and Bence Jones protein (kappa) in urine samples. The bone marrow examination showed an increased number of pathological plasma cells (34. 5%). Multiple osteolytic lesions were evident on X-ray films. A diagnosis of multiple myeloma (MM) was made. He had exudative erythematous skin lesions on his back. His serum was positive for antibody to ATLA. A biopsy specimen from the skin lesions showed Pautrier's micro-abscess which were filled with Leu 3a positive T lymphocytes. 159 base pairs of human T cell leukemia virus I (HTLV-I)/pX position was identified from a cutaneous sample utilizing the polymerase chain reaction method. Thus, a diagnosis of MM superimposed on adult T cell lymphoma was made. An extensive search failed to find any cases complicated with these two diseases except a report by Tagawa et al. concerning a patient with ATL who developed IgA (kappa) MM during a five year follow up. Therefore, this is the first reported case of MM superimposed on ATL.     

Adult T-cell leukemia with massive melena due to marked gastrointestinal involvement

A 60-year-old man born in Okinawa was admitted to our hospital because of epigastralgia. Physical examination revealed general lymphadenopathy, mild hepatomegaly and skin eruption. The peripheral blood leukocyte count was 168,600/microliters, with 93% abnormal lymphocytes showing convoluted or lobulated nuclei. Anti HTLV-1 antibody was positive with titer of 1: 1280 (PA). Leukemic cells had typical ATL cells' surface markers (OKT3; 97.2%, T4; 93.3%, T8; 2.8%, OKIA1; 39.6%, IL-2R; 41.8%) and complete monoclonal HTLV-1 provirus DNA. Endoscopic examination with biopsy revealed massive involvement of ATL cells into gastric mucosa. In the course of the treatment, he had extremely massive melena, and was saved by emergency operation. Multiple ulcers were found in the resected colon. Histological examination showed the marked infiltration of the ATL cells into the mucous or submucous membrane. Thereafter, he was treated well with ALG (Anti Lymphocyte Globulin), until hypercalcemia occurred. He died of acute renal failure after hypercalcemia.     

Identification of human T cell leukemia virus in a Japanese patient with adult T cell leukemia and cutaneous lymphomatous vasculitis.

We have identified a Japanese patient with adult T-cell leukemia (ATL) whose T cells in vitro produced the human T-cell leukemia virus (HTLV). This patient presented with lymphomatous arthritis and leukemia and subsequently developed skin lesions. Skin invasion by malignant T-cells was angiocentric and produced vessel wall destruction, resulting in necrotic cutaneous tumor nodules. Malignant T cells in peripheral blood, skin, and joint prior to culture in vitro did not express p19 HTLV-associated antigen. However, by electron microscopy, intracellular type C viral particles were seen in skin-infiltrating T cells. Peripheral blood malignant cells after 7 days in culture with T-cell growth factor-supplemented media expressed p19 antigen, and type C virus particles were seen by electron microscopy to be budding from malignant T lymphocytes. Mitomycin-C-treated peripheral-blood T cells induced the transformation of cord blood T cells into HTLV-infected p19+ T cells. The demonstration of HTLV in malignant T cells from our patient confirms the association of HTLV with Japanese adult T-cell leukemia. Moreover, HTLV may be associated with a vasculitis-arthritis syndrome.     

Epstein-Barr virus-associated B cell lymphoproliferative disorder complicated in adult T-cell leukemia

Adult T-cell leukemia (ATL) is accompanied by remarkably impaired cellular immune responses. Reports on the simultaneous development of ATL and Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPD) are, however, quite rare. A 53-years-old man was admitted to our hospital because of multiple bilateral pulmonary nodules, skin rash, lymphadenopathy, and hypercalcemia. The smear preparation of peripheral blood demonstrated pathological lymphocytes with lobulated nuclei. They expressed CD2, CD3, and CD25, but did not express either CD4 or CD8. In addition, he was positive for Human T-cell leukemic virus type-I (HTLV-I), and monoclonal integration of HTLV-I provirus was detected in peripheral blood. Unexpectedly, inguinal lymph node biopsy showed polyclonal proliferation of EBV-positive large and bizarre-shaped B cells, and monoclonal growth of large abnormal T cells. He was diagnosed as having acute type ATL complicated by EBV-LPD. Chemotherapy for ATL effectively decreased the tumor burden of ATL, but persistent high fever developed suddenly on the 68th day after admission, and he died of multi-organ failure with severe metabolic acidosis. At the time of multi-organ failure, viral load had increased strikingly, suggesting that the progression of EBV-LPD might have been responsible for multi-organ failure in this case.     

Successful treatment of adult T-cell leukemia with interferon-alpha-2b by systemic and local administration

A 59 years old woman, born in Fukuoka Prefecture, was admitted to our hospital in Aug, 1988 because of diarrhea, fever and skin eruption. Physical examination revealed systemic lymphadenopathy and hepatosplenomegaly. The white blood cell count was 11,200/microliters with 28% atypical lymphocytes with convoluted nuclei. Mild anemia, thrombocytopenia and hypercalcemia were also observed. Antibody against the adult T-cell leukemia (ATL) associated antigen in serum was positive. OKT 4/8 ratio was high. A diagnosis of ATL was made. Because of the complications of pneumonia and herpes simplex, systemic chemotherapy was not given, and interferon (IFN)-alpha-2b was intramuscularly injected daily from Oct, 1988, resulting in the disappearance of atypical lymphocytes and improvement of skin lesions. The effect of IFN therapy lasted for three months, followed by increase of atypical lymphocytes. Although the patient became refractory to systemic IFN therapy, local injection of IFN into a buccal tumor infiltrated with atypical lymphocytes resulted in its regression of size. In spite of continued administration of IFN, the patient died of pneumonia in Jan, 1989.     

Preleukemic state of adult T cell leukemia: abnormal T lymphocytosis induced by human adult T cell leukemia-lymphoma virus

We report the clinical, hematologic, and immunologic features of 18 preleukemic adult T cell leukemia (pre-ATL) cases with abnormal T lymphocytosis induced by human adult T cell leukemia-lymphoma virus (HTLV/ATLV). The patients were from the Nagasaki district, which is one of the most endemic areas of ATL in Japan. Pre-ATL is a subclinical T cell abnormality differing from ATL. It is characterized by an insidious onset and appearance of abnormal T lymphocytes (10% to 40%) in the peripheral blood without clinical symptoms except for a few cases transiently presenting fever, skin eruptions, and slight lymphadenopathies. Most abnormal T lymphocytes were small and mature with incised or lobulated nuclei and formed E rosettes with sheep RBCs. Virologic and biomolecular analysis revealed that all cases were infected with HTLV, and proviral DNA was integrated in host lymphocytes from 12 of the 14 cases examined. Furthermore, the lymphocyte populations, including abnormal T lymphocytes, were monoclonal with respect to the site of the provirus integration. Abnormal T lymphocytosis persisted from one to more than seven years in six cases, three of which developed ATL after a one- to five-year pre-ATL stage, whereas abnormal T lymphocytes spontaneously decreased in the other seven patients. However, HTLV-infected monoclonal lymphocytes were detected in four cases examined, even after most of the abnormal T lymphocytes had disappeared. Moreover, the same clonally provirus- integrated lymphocytes persisted in two of four cases not only during the course of abnormal lymphocytosis, but also in the subsequent almost- normal blood. These results indicate that the majority of the cases were in a pre-ATL state with a potential to develop ATL.     

Adult T-cell leukemia (ATL) cells which express neural cell adhesion molecule (NCAM) and infiltrate into the central nervous system

We encountered a patient with adult T-cell leukemia/lymphoma (ATL) which expressed neural cell adhesion molecule (NCAM). The tumor cells markedly infiltrated the central nervous system (CNS) during the course of the ATL. The patient died 20 months after disease onset, which was considered to be early in the course. During the invasion of the CNS, the surface phenotype of the peripheral blood ATL cells by flow cytometric analysis was CD2+, CD3+, CD4+, CD7-, CD8-, CD16-, NCAM (CD56)+, HLA-DR-. We speculate that the infiltration of ATL cells into the CNS was closely related to the expression of the NCAM in this patient.     

Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis.

Two hundred twelve Italian patients with genetic hemochromatosis (181 men, mean age 50 +/- 11 yr; and 31 women, mean age 49 +/- 10 yr) were followed for a median period of 44 mo (range = 3 to 218 mo). Alcohol abuse was present in 31 subjects (15%), and chronic HBV and HCV infection were seen in 19 (9%) and 35 (24%) of 145 cases tested, respectively. Twenty-four patients (11%) had concomitant beta-thalassemia trait. Liver biopsy revealed cirrhosis in 146 and a noncirrhotic pattern in the other 66. Perls' stain was degree III in 37 patients and IV in 171 patients. One hundred eighty-five patients underwent weekly venesection, and iron depletion was achieved in 122 cases after total iron removal of 3 to 41 gm. Death occurred in 44 patients after 3 to 198 mo and was due to hepatocellular carcinoma in 20 cases, liver failure in 10, extrahepatic cancer in six, heart failure in three and hemochromatosis unrelated causes in five. Cancer has developed in seven other patients still alive (hepatocellular in five and extrahepatic in two). No deaths were observed among noncirrhotic patients; cumulative survival rates in cirrhotic patients were 85%, 75%, 60% and 47% at 3, 5, 8 and 10 yr, respectively. Univariate analysis in the 146 cirrhotic patients showed that age greater than 60 yr, alcohol abuse, cardiomyopathy, skin pigmentation, portal hypertension, hypoalbuminemia, hypergammaglobulinemia and Child class B or C had significant negative prognostic value. At multivariate analysis, only alcohol abuse, gamma-globulins greater than 2.0 gm/dl and Child class B or C maintained their negative prognostic values (p less than 0.01, hazard ratio 2.7; p less than 0.001, hazard ratio 2.8; and p less than 0.001, hazard ratio 4.3, respectively).     

The Spectrum of Paraneoplastic Cutaneous Vasculitis in a Defined Population: Incidence and Clinical Features

Cutaneous vasculitis may be associated with malignancies, and may behave as a paraneoplastic syndrome. This association has been reported in a variable proportion of patients depending on population selection. We conducted the current study to assess the frequency, clinical features, treatment, and outcome of paraneoplastic vasculitis in a large unselected series of 766 patients with cutaneous vasculitis diagnosed at a single university hospital.Sixteen patients (10 men and 6 women; mean age ± standard deviation, 67.94 ± 14.20 yr; range, 40–85 yr) presenting with cutaneous vasculitis were ultimately diagnosed as having an underlying malignancy. They constituted 3.80% of the 421 adult patients. There were 9 hematologic and 7 solid underlying malignancies. Skin lesions were the initial clinical presentation in all of them, and the median interval from the onset of cutaneous vasculitis to the diagnosis of the malignancy was 17 days (range, 8–50 d). The most frequent skin lesions were palpable purpura (15 patients). Other clinical manifestations included constitutional syndrome (10 patients) and arthralgia and/or arthritis (4 cases). Hematologic cytopenias (11 cases) as well as immature peripheral blood cells (6 cases) were frequently observed in the full blood cell count, especially in those with vasculitis associated with hematologic malignancies.Specific treatment for vasculitis was prescribed in 10 patients; nonsteroidal antiinflammatory drugs (4 patients), corticosteroids (3 patients), chloroquine (1 patient), antihistamines (1 patient), and cyclophosphamide (1 patient). Ten patients died due to the malignancy and 6 patients recovered following malignancy therapy. Patients with paraneoplastic vasculitis were older, more frequently had constitutional syndrome, and less frequently had organ damage due to the vasculitis than the remaining patients with cutaneous vasculitis.In summary, cutaneous paraneoplastic vasculitis is an entity not uncommonly encountered by clinicians. The most common underlying malignancy is generally hematologic. In these cases the presence of cytopenias and immature cells may be red flags for the diagnosis of cancer. In patients with paraneoplastic cutaneous vasculitis, the prognosis depends on the underlying neoplasia.     

Ocular manifestations in adult T-cell leukemia/lymphoma

 Ocular manifestations of adult T-cell leukemia/lymphoma (ATL) are rare events. However, several ocular lesions which resulted from human T-cell leukemia virus type I (HTLV-I) infection have been reported, including direct infiltration of ATL cells, cytomegalovirus retinitis, and HTLV-I-associated uveitis (HAU). The aim of this study was to characterize ocular involvement in ATL and to correlate these lesions with HTLV-I proviral DNA integration. Three patients with acute-type ATL and ocular lesions were evaluated hematologically and ophthalmologically. Analysis of HTLV-I proviral DNA was carried out with a standard Southern blot technique using DNA from abnormal lymphocytes in peripheral blood. Two patients developed intraocular lesions located within intermediate and/or posterior segments which were caused by infiltration of ATL cells. Ocular lesions in one patient, which were localized to the anterior-intermediate segment, closely resembled those of HAU. Analysis of HTLV-I proviral DNA revealed multiple integrations in all three patients. The present study indicated heterogeneity in ocular manifestations of ATL. Multiple HTLV-I proviral DNA integrations may be associated with intraocular involvement in this disease. Received: 30 October 1996 / Accepted: 23 January 1997     

Myelofibrosis with myeloid metaplasia in adult individuals 30 years old or younger: presenting features, evolution and survival

Myelofibrosis with myeloid metaplasia (MMM) usually affects older people and is associated with a median survival of 3.5-5 yr. Survival of MMM patients 55 yr old or younger is longer, but there is no information on the youngest subset. The presenting features, evolution and survival were analyzed in 9 patients with MMM aged 30 yr or less, representing 2.8% of two series including 323 cases. Age ranged from 17 to 30 yr; 3 patients were males and 6 females. Five patients were asymptomatic and none had constitutional symptoms. Anemia was observed in 4 patients, being severe in only one. The WBC count was normal in 7 patients and 2 had mild leukocytosis; moderate thrombocytosis was observed in 7 patients. No patient showed blood blast cells or bone marrow cytogenetic abnormalities. With a median follow-up of 6.8 (range 0.8-28) yr, 2 patients died 10.7 and 9.9 yr from diagnosis, one from complications of bone marrow transplantation performed after progression of the disease and the other from gastrointestinal bleeding secondary to portal hypertension. Among remaining patients, one developed Budd-Chiari syndrome, another was lost to follow-up at 3 yr, and 5 remain asymptomatic and currently without treatment (one had been splenectomized at diagnosis). These results indicate that in most young adults with MMM the disease presents without adverse prognostic factors and may remain stable for years, which may be of interest when considering the treatment of such patients.     

Adult T-Cell Leukemia in a Liver Transplant Recipient That Did Not Progress after Onset of Graft Rejection

A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T-cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.     

Graft-versus-adult T-cell leukemia/lymphoma effect following allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven effective in adult T-cell leukemia/lymphoma (ATL) patients. To study the graft-versus-ATL (Gv-ATL) effects after allo-HSCT, we analyzed 21 ATL patients who had been treated at our hospital. Of these, 18 had acute-, 2 had lymphoma- and 1 had chronic-type ATL; at allo-HSCT, seven patients were in CR, one was in PR, five had stable disease (SD) and eight had progressive disease (PD). Disease state after allo-HSCT was CR in 14, PR in 3, SD in 1 and PD in 3 patients. Among 15 patients who survived longer than 100 days, ATL relapsed in 10 patients, skin relapsed in 9 patients and 5 had relapsed on the skin alone. After we discontinued immunosuppressant therapy in these 10 patients, 8 manifested GVHD; ATL was ameliorated to CR in 6 patients. Donor lymphocytes were infused into two patients who did not show GVHD; one obtained CR. In five patients with skin relapse alone, four patients achieved CR following the discontinuation of the immunosuppressants. Our results demonstrate that relapse of ATL after allo-HSCT tends to develop on skin, and Gv-ATL effects played a critical role in the outcome of allo-HSCT for ATL.     

Spontaneous remission of acute myeloid leukemia after infection and blood transfusion associated with hypergammaglobulinaemia

 Spontaneous remissions of acute myeloid leukemia (AML) have been documented in association with infection as well as blood transfusions. Activation of the immune system including an increased number of NK cells and cytokine release have been implicated in the mechanism of this phenomenon. We have observed spontaneous remissions in two patients with AML (one with a t(8;21)-positive M2, one with M5b), both occurring after infection and blood transfusions. The bone marrow showed a reduction of blast cells from 65% to 2% or 40% to 1%, respectively. Remission was accompanied by a marked polyclonal hypergammaglobulinemia in both cases (IgG values of 6420 and 2160 mg/dl, IgA of 802 and 811 mg/dl, respectively). A concomitant increase in bone marrow plasma cells was observed in both patients. Reduction of AML1/ETO PCR positivity from one-step to two-step PCR (approximately 100-fold) was documented in the patient with a t(8;21), while a regression of lymph node and skin leukemic infiltrations occurred in the patient with M5b. One patient relapsed after 4 months, at a time when his serum immunoglobulin levels had markedly decreased. The other patient is in continuous remission after 14 months. These cases suggest a potential role for a humoral immune response in the mechanism of spontaneous remission. Received: 18 March 1996 / Accepted: 2 July 1996     

Chronic graft versus host disease: a syndrome of disordered immunity.

A chronic, debilitating syndrome related to graft-versus-host disease (GVHD) has been recognized in long-term survivors following allogeneic bone marrow transplantation. In six of 20 marrow graft recipients who survived for more than one year after receiving a transplant, this complication developed; they were studied to better define the syndrome. There was no association between the sex of either donor or recipient, HLA type, blood group, conditioning regimen or marrow cell dose and subsequent development of chronic GVHD. All six patients had mild to moderate manifestations of acute GVHD following prompt engraftment. Chronic GVHD was characterized in each patient by progression to scleroderma-like skin involvement with hyperkeratosis, reticular hyperpigmentation, atrophy with ulceration and fibrosis with limitation of joint movement. A sicca syndrome was prominent in five patients. Four patients had idiopathic interstitial pneumonitis. Infectious complications were frequent, and DNA viral infections were prominent. Autoimmune hemolytic anemia was present in three patients, and one patient had antinuclear antibody (ANA). A spectrum of immune abnormalities was observed including hypergammaglobulinemia, immunoglobulin M (IgM) paraprotein, elevated circulating immune complexes, plasma cell hyperplasia, lymphocytotoxic antibodies and autoantibodies to autologous or donor lymphocytes. Despite clinical similarity to collagen vascular diseases, none of these patients had anti-DNA antibodies or antibodies to smooth muscle, thyroid or extractable nuclear antigens. In one patient, a skin graft from the marrow donor remained healthy despite progressive involvement in recipient skin, whereas unrelated skin grafts were rejected. Immunosuppressive therapy and plasmapheresis have not been effective. Four patients have died (median survival 458 days from transplantation). Chronic GVHD appears to be a syndrome of disordered immune regulation features of immunodeficiency and autoimmunity.