ABSTRACT: When oncologists diagnose patients suspected of lymphoid malignancy, it is important to consider the possibility of adult T-cell leukemia/lymphoma (ATL) with a routine check for serum human T-cell lymphotropic virus type 1 (HTLV-1) antibody. The following points are essential for the diagnosis of ATL: (1) cytologically or histologically proven peripheral T-cell malignancy, and (2) positivity for anti-HTLV‑1 antibody. When a patient is diagnosed with ATL, it is important to make an accurate diagnosis of clinical subtype in order to make appropriate treatment decisions. For patients with smoldering or chronic type ATL, close observation with careful monitoring for opportunistic infections is recommended. For patients with the acute or lymphoma type requiring therapy, enrollment in a clinical trial is recommended. When there is no active trial or the patient is ineligible for a trial, we recommend intensive chemotherapy used for aggressive non-Hodgkin lymphoma such as the LSG15 regimen (VCAP-AMP-VECP) based on a recent phase III study. Because most patients with ATL are not curable with current chemotherapy regimens, it is reasonable to consider the applicability of allogeneic stem cell transplantation in patients who show responses to chemotherapy. For relapsed or refractory patients, enrollment in a new-agent trial should be considered in addition to stem cell transplantation.
Adult T-cell leukemia/lymphoma (ATL) is defined as a histologically or cytologically proven peripheral T-cell malignancy associated with a retrovirus, human T-cell lymphotropic virus type I (HTLV-1). Southwestern Japan is the district with the highest prevalence of HTLV-1 infection and the highest incidence of ATL in the world. A high prevalence of HTLV-1 infection is also found in the Caribbean islands, tropical Africa, South America, and northern Oceania.
It is estimated that approximately 1.2 million HTLV-1–infected individuals reside in Japan, and the annual incidence of ATL is estimated to be approximately 700 in Japan. The annual rate of ATL development among HTLV-1 carriers older than 40 years is estimated at 1.5 per 1,000 in males and 0.5 per 1,000 in females. The cumulative risk of the development of ATL among HTLV-1 carriers is estimated to be 2.5% during a 70-year lifespan. In a national survey in Japan, the mean age of patients with ATL was 57.6 years. Patients in areas outside Japan are somewhat younger, with an overall mean age in the mid-40s. There is a marked increase in HTLV-1 prevalence with age until 70 years. A major reason for the increase in seroprevalence with age appears to be the decreasing prevalence of HTLV-1 in the population with time.
Potential Strategies to Eliminate ATL
HTLV-1 is transmitted via at least three routes: (1) mother-to-child transmission, mainly by breast-feeding; (2) sexual transmission, commonly from males to females; and (3) blood-borne transmission. The overall infection rate of HTLV-1 in children by seropositive mothers is estimated to be 10% to 30%.
Several intervention trials have been conducted in Japan. The seropositive mothers were advised to refrain from breast-feeding. To prevent HTLV-1 transmission through blood transfusions, serologic screening for HTLV-1 in all blood donors has been conducted in Japan since 1986. Since then, no episodes of seroconversion in transfusion recipients have been recognized.
Typically, the neoplastic cells in the peripheral blood are markedly polylobated and have been termed flower cells, although the cytologic spectrum of ATL is diverse. These cytologic features are most evident in the acute type of ATL. Lymph nodes typically show diffuse architectural effacement. Small pleomorphic lymphoid cells may predominate or may be admixed with larger cells. The transformed cells may have more pleomorphic nuclear features. Giant cells with convoluted or cerebriform nuclear contours may be present.
Skin involvement is seen in more than 50% of patients. The skin lesions are clinically and histologically diverse, and may mimic inflammatory disorders in some patients. Other frequent sites of involvement include lung and cerebrospinal fluid. The pulmonary infiltrates are generally patchy and interstitial, without formation of tumor nodules. Involvement of the central nervous system is usually manifested as meningeal infiltration without parenchymal lesions.
The neoplastic cells are CD4-positive (CD4+) T cells that strongly express the interleukin-2 receptor (IL-2R) alpha subunit, CD25. In addition, CD3 and other mature T-cell antigens (CD2, CD5) are usually expressed. Recent studies have suggested that the cells of ATL may be the equivalent of Treg cells.
The onset of ATL is preceded by a long period of latency, frequently lasting longer than 4 decades. In addition, only up to 5% of all individuals infected with HTLV-1 develop ATL. The age-specific occurrence of ATL suggested a multistep carcinogenesis model.
Initial steps depend on viral gene products, among which a viral regulatory protein, Tax, plays a pivotal role. Tax was shown to be the major viral protein with oncogenic potential. Tax also exerts its pleiotropic functions through direct interaction with numerous cellular proteins, resulting in a unique phenotype of the infected cells. Antisense transcripts of the HTLV-1 provirus were reported. The transcript can encode a novel basic leucine zipper protein, named HBZ, which interacts with CREB2 and c-Jun and suppresses the activity of Tax and activator protein-1, respectively. Several isoforms of HBZ transcripts were reported to be steadily expressed in HTLV‑1–infected cells and ATL cells. The functions of these transcripts and putative protein in the context of cellular transformation are now under investigation.[7,8]
Clinical Subtypes of Disease
Based on a nationwide survey of 854 patients with ATL in Japan, the Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group (JCOG) proposed diagnostic criteria for the four clinical subtypes. The leukemic subtypes include the acute type, with a rapidly progressive course and most of the characteristic features of ATL—generalized lymphadenopathy, hepatosplenomegaly, skin involvement, hypercalcemia, and organ infiltration. The symptoms and signs include abdominal pain, diarrhea, ascites, pleural effusion, cough, sputum, and chest x-ray abnormalities. The smoldering type shows an indolent course (expected median survival > 5 years) and 5% or more of leukemic cells in the peripheral blood but may also include skin involvement. The chronic type, with absolute lymphocytosis (≥ 4 × 109/L) frequently showing flower cell morphology, is occasionally associated with skin involvement and lymphadenopathy, and also shows a relatively indolent course (expected median survival = 24.3 months). The lymphoma type is comprised of patients presenting with the manifestations of lymphoma without leukemic cells. In ATL, the clinical subtype is more important than the Ann Arbor stage for predicting prognosis and deciding treatment in each patient.
Clinical Aspects of Disease
ATL—particularly the aggressive forms (acute and lymphoma types)—has been found to infiltrate the stomach in 29% and the intestine in 25% of patients at autopsy. Patients with ATL experience a variety of abdominal symptoms, such as nausea, vomiting, abdominal fullness, and diarrhea, which may be attributable to the infiltration by neoplastic cells, but because of the associated immunodeficiency, opportunistic infections such as Strongyloidiasis may complicate the course.
Hepatic involvement may be found in 31% of patients with the acute or lymphoma type and is not infrequently manifested by jaundice (30%) and hepatic enzyme elevations (53%). Pulmonary complications in 18% of patients are due to leukemic infiltration in one-half of the patients and to infections with a variety of bacterial and opportunistic organisms in the remaining one-half. Central nervous system involvement, mostly leptomeningeal involvement, occurs in approximately 10% of patients with ATL. The initial symptoms include muscle weakness, altered mental status, paresthesia, headache, and urinary incontinence, which are occasionally difficult to differentiate from those caused by the HTLV-1–associated neurologic disorder, tropical spastic paraparesis (TSP)/HTLV-1-associated myelopathy (HAM).
Approximately 26% of 854 Japanese patients with ATL had active infections at diagnosis. The incidence was highest in the chronic and smoldering types (36%) and lower in the acute (27%) and lymphoma types (11%). The encountered infections were bacterial in 43%, fungal in 31%, protozoal in 18%, and viral in 8% of patients. The immunodeficiency at presentation in ATL patients can be exacerbated by cytotoxic chemotherapy.
Laboratory findings also depend on the clinical subtype. Leukocytosis is found in patients with the acute or chronic type at presentation, exhibiting characteristic atypical lymphoid cells with marked polymorphic nuclei or so-called flower cells. Most patients (83%) with the acute or lymphoma type have elevated serum lactate dehydrogenase (LDH) levels. The most striking laboratory finding in patients with ATL is hypercalcemia, which was found in 32%.
In ATL, age (≥ 40 years), poor performance status (≥ 2), high LDH, hypercalcemia, and four or more involved lesions were reported to be unfavorable prognostic factors.[9,10] For patients with the chronic type, the major prognostic factors are serum LDH, albumin, and blood urea(Drug information on urea) nitrogen (BUN). Patients with the chronic type and normal values for these three factors have a favorable prognosis similar to the smoldering type. In contrast, patients with the unfavorable chronic type who have an abnormal value in at least one of these three factors would be candidates for cytotoxic chemotherapy.
It is recommended that patients with the favorable chronic or smoldering type of ATL be carefully monitored for infectious complications and signs of disease progression to the acute or lymphoma type.
Without treatment, most previously untreated patients with aggressive forms of the disease (acute or lymphoma type) die within weeks or months of the diagnosis. Most patients with the smoldering type live well without chemotherapy for a considerable time (expected median survival > 5 years).
Approximately two-thirds of patients with chronic-type disease die within approximately 2.5 years from diagnosis. Patients with the lymphoma type have unfavorable prognoses, with a median survival of 10.2 months. The most aggressive form of ATL is the acute type, associated with a median survival of 6.2 months. The projected 4-year survival rates of patients with the lymphoma and acute types are only 5%.
The clinical subtype clearly determines the prognosis of each patient with ATL. In patients with smoldering- or chronic-type disease, the expected time to evolution to the acute or lymphoma type (and the incidence of that conversion) remain unclear, partly due to the lack of prospective studies. However, in a recent long-term follow-up study on 90 patients with indolent ATL (65 chronic type and 25 smoldering type) at a single institution, the median survival was 4.5 years, and the projected 5-, 10-, and 15-year survival rates were 47%, 23%, and 13%, respectively.