Adult T-Cell Leukemia/Lymphoma

Summary of Key Points

• Definition

• Adult T-cell leukemia/lymphoma (ATLL) is a distinct mature peripheral T-cell malignancy associated with human T-cell leukemia/lymphotropic virus type I (HTLV-I).

• Virology and Pathogenesis

• HTLV-I is reverse-transcribed into DNA and randomly integrated into the host cell.

• The HTLV-I genome encodes two unique regulatory proteins—Tax and Rex—responsible for viral expression and cellular transformation. Tax trans -activates viral and cellular genes that could be involved in the pathogenesis of ATLL. HTLV-I basic leucine zipper (HTLV-I bZIP; HBZ) is an antisense transcript of HTLV-I, is steadily expressed in ATLL cells, and interacts with several host genes and suppresses the activity of Tax.

• Epidemiology

• A major cluster of HTLV-I–infected individuals and patients with ATLL exists on the southwest coast of Japan, where approximately 1.1 million people are infected with the virus.

• Other clusters have been noted in the Caribbean islands (African), tropical Africa (African), South America (Mongoloid), and northern Oceania (Melanesian).

• HTLV-I is transmitted from mother to child through breastfeeding, by sexual contact, and by bloodborne transmission.

• The estimated cumulative risk of the development of ATLL in HTLV-I–positive individuals is about 3% after transmission from their mothers.

• Clinical Manifestations

• Patients with ATLL show diverse clinical features. Four clinical subtypes are recognized: acute, lymphoma, chronic, and smoldering.

• The typical manifestations of acute-type ATLL include circulating neoplastic cells in the peripheral blood, generalized lymph node swelling, hepatosplenomegaly, skin involvement, opportunistic infections, and hypercalcemia.

• Histopathology

• Leukemic cells in the peripheral blood characteristically show markedly polylobated nuclei, so-called flower cells. The immunophenotype of the neoplastic cells are CD4/CD25/CCR4+ and CD8− in most cases.

• All histopathological specimens show findings of a mature peripheral T-cell lymphoma of various recognized subtypes.

• Diagnosis

• ATLL is suspected when the aforementioned characteristic clinical manifestations or the cytologic findings of leukemic cells in the peripheral blood are recognized.

• Morphologic and immunophenotypic analyses of neoplastic cells in peripheral blood or tumor lesions and a serologic assay against HTLV-I are required for the clinical diagnosis of ATLL.

• The demonstration of the monoclonal integration of HTLV-I proviral DNA in the neoplastic cells leads to a definite diagnosis of ATLL but is not generally available or required.

• Treatment and Prevention

• An accurate diagnosis of the clinical subtype is vital for appropriate decisions regarding treatment.

• Intensive chemotherapies combining agents used in the treatment of non-Hodgkin lymphoma are given to patients with the acute or lymphoma subtype of ATLL; however, most patients with ATLL do not achieve cure with current chemotherapy regimens.

• Further efforts to incorporate promising or new, innovative treatment modalities, such as interferon–zidovudine therapy, new anticancer agents, monoclonal antibody therapy, molecular-targeting therapy, and allogeneic hematopoietic stem cell transplantation, are needed for the establishment of risk-adopted therapy.

• Prevention of HTLV-I infections has been achieved in some endemic areas by screening for HTLV-I among blood donors and the recommendation that mothers who are carriers refrain from breastfeeding. Prevention of ATLL among HTLV-I carriers has not been achieved, although several risk factors have been identified.