ATLL is associated with the human retrovirus HTLV-1, with clonal integration of the HTLV-1 virus in the T cells.1
Nonviral causes of ATLL are not part of the World Health Organization definition of this disorder and may result from failure to serologically detect anti-HTLV-1 antibodies. summarizes the key clinical characteristics of ATLL. ATLL is subclassified into 4 groups: acute, lymphomatous, chronic and smouldering. The acute form typically involves multiple organs (including the central nervous system), the skin, a leukemic peripheral blood picture, hepatosplenomegaly and systemic lymphadenopathy. Lytic bone lesions are often present with hypercalcemia. The peripheral blood leukemic cells are multilobated lymphocyte “flower cells,” with a T-helper cell immunophenotype and expression of CD2, CD3, CD4, CD5 but not CD8. CD7 expression is often lost. The strong expression of CD25 (interleukin-2 receptor) is characteristic of ATLL and helps to distinguish this disorder from cutaneous T-cell lymphoma. Acute ATLL is an aggressive disease, with a median survival time of 6 months. Patients with acute ATLL are immunocompromised and at risk of disseminated disease with Strongyloides
; therefore, investigation for Strongyloides stercoralis
should be part of the routine work-up in cases of the more aggressive forms of ATLL. The lymphomatous type of ATLL is dominated by generalized lymphadenopathy, without peripheral blood involvement. Hepatosplenomegaly and hypercalcemia are observed. The clinical course is aggressive, with a median survival time of 10 months. The chronic and smouldering forms of ATLL are associated with prolonged survival, with more than 10% and less than 5% circulating leukemic cells, respectively.
Transmission of HTLV-1 may be horizontal (through transfusion of cellular blood products, sexual intercourse or sharing of contaminated needles) or vertical (transplacental, intrapartum or through breast-feeding). The clinical manifestations of acute infection with HTLV-1 are not well documented, but they may be asymptomatic or similar to a mild, flu-like illness. In the natural history of this infection, the majority of people infected with HTLV-1 do not go on to experience clinically significant complications. ATLL develops in about 1% to 4% of these people, with a latency of 20 to 30 years, and HTLV-1– associated myelopathy/tropical spastic paresis (HAM/TSP) develops in 0.1% to 1%, with a slightly shorter latency period. Other clinical syndromes associated with HTLV-1 include arthropathy, uveitis, infectious dermatitis in children and Sjögren's syndrome.
HTLV-1 infection is endemic in the Caribbean, southwestern Japan (especially the island of Kyushu), parts of Central and South America, central Asia, the Middle East, Melanesia and sub-Saharan Africa ().1
Infection with the HTLV-1 virus has also been reported in circumpolar populations, including Aboriginal people in Alaska, the Lapps of Sweden, the Nivkhi of Eastern Russia and, most recently, the Inuit people of Nunavut.2
In cases where HTLV-1 strains in these populations have been examined genetically to determine their phylogenetic affinities (including the present cases), they have been shown to belong to a large, globally distributed genealogic cluster termed “Cosmopolitan subclade A.” This could reflect the relatively recent common ancestry of circumpolar peoples.3
Fig. 3: Regions of endemic human T-cell lymphotropic virus type 1 (HTLV-1) infection (brown regions). Populations of proposed common ancestry (where HTLV-1 virus of the Cosmopolitan clade a, transcontinental subgroup A, has been identified) (green regions). (more ...)
Treatment with combined chemotherapy used to treat non-Hodgkin's lymphoma is usually ineffective in cases of acute ATLL. Antiviral medications, including α-interferon and zidovudine, are useful, but the response is usually transient. Follow-up of asymptomatic patients infected with HTLV-1 is warranted. Recommendations for clinical and laboratory follow-up are summarized in . These may be performed every 6 months and are designed to elicit the earliest manifestations of ATLL or HAM/TSP. DNA testing to assess proviral load, clonal integration of the viral genome and antigenic drift may also provide additional information concerning the risk of clinically significant syndromes. A first step in the prevention of ATLL is testing for HTLV-1 antibodies in endemic areas. Measures may then be directed to limit the impact of HTLV-1 infection. Breast-feeding for less than 7 months has been shown to reduce the prevalence of infection to the same level as that among infants who are not breast-fed at all. Mothers infected with HTLV-1 who shorten the duration of breast-feeding to the first 6 months of life may limit vertical transmission while retaining the overall benefits of breast-feeding. The likelihood of transmission of HTLV-1 to the baby is also reduced by freezing and rethawing breast milk. Transmission through sexual intercourse is mostly male to female, and the use of condoms may decrease the risk. In the future, there may be a role for antiretroviral agents and monoclonal antibody therapy (alemtuzumab) in reducing the proviral load in HTLV-1 carriers. High proviral load has been linked to an increased risk of transmission to others and an increased risk of HAM/TSP and ATLL. Preliminary findings of studies suggest that the Tax transactivator viral protein may be a suitable target for vaccination development.
Simone Fahim Robert Prokopetz Robert Jackson Division of Dermatology Carolyn Faught Division of Clinical Hematology Anne E. McCarthy Division of Infectious Diseases Department of Internal Medicine The Ottawa Hospital Ottawa, Ont. Anton Andonov Michael Coulthart National Microbiology Laboratories Winnipeg, Man Zohra Daw Bernhard Olberg Antonio Giulivi Ruth Padmore Division of Hematology and Transfusion Medicine Department of Pathology and Laboratory Medicine The Ottawa Hospital Ottawa, Ont.