Comment
Etiology
First described in 1977, ATLL is an uncommon neoplasm of mature T cells.6 The etiology is associated with infection by the retrovirus HTLV-1, which is endemic in Southern Japan, the Caribbean, Central and West Africa, and Central and South America, with increasing incidence in areas of the United States with large immigrant populations.7 The incidence of ATLL among all registered lymphoma cases from 2003 to 2008 in Japan was 8.3% compared to 0.2% in the United States.7
Transmission of HTLV-1
Human T-lymphotropic virus 1 is a retrovirus most commonly found in CD4+T cells and can be transmitted through breast milk, sexual intercourse, and blood exposure (eg, blood transfusion), with breastfeeding and blood exposure being the most common.8-10 Human T-lymphotrophic virus 1 has been described as the causative agent for 3 entities: (1) ATLL, (2) a nervous system degenerative disorder known as HTLV-1–associated myelopathy or tropical spastic paraparesis, and (3) HTLV-1 uveitis.5,11 It is thought that 10 to 20 million individuals worldwide are infected with HTLV-1.12
The evolution from infection with HTLV-1 to ATLL is thought to involve multiple steps.13,14 Those who contract the virus later in life rarely, if ever, develop ATLL, suggesting that this progression requires considerable time to evolve to carcinogenesis. More than 90% of those infected with HTLV-1 remain asymptomatic, while only 2% to 3% of women and 6% to 7% of men develop ATLL with a median incubation period greater than 15 to 20 years.7
Subtypes
Adult T-cell leukemia/lymphoma has been divided into 4 clinical subtypes based on clinical presentation and prognosis.15 The acute type is more aggressive and has a poorer prognosis, while the chronic and smoldering types have a more indolent course. The smoldering variant largely has only cutaneous involvement with less than 1% of the peripheral leukocytes being atypical lymphocytes.16 A cutaneous subtype in which few to no leukemic cells are present also has been described and may overlap with the smoldering variant.The cutaneous variant has been further classified into 2 subtypes, tumoral and erythematopapular, with the tumoral subtype carrying a worse prognosis.17,18 Clinically, 39% to 57% of ATLL cases have skin involvement, with nearly one-third reporting skin manifestations as the first symptom.19,20 The cutaneous manifestations vary greatly and may include papules, plaques, nodules, tumors, erythematous patches, or erythroderma.4,21 In addition to skin manifestations, most patients with acute ATLL demonstrate leukemia, lymphadenopathy, organomegaly, and hypercalcemia.22
Histopathology
Histologically, both the smoldering and chronic forms of tumoral or erythematopapular ATLL demonstrate a cutaneous, dermal, or subcutaneous infiltrate of small- to medium-sized CD4+ T cells with histiocytes and admixed granulomas.4 Epidermotropism and Pautrier microabscesses often are limited or absent but can be seen. The neoplastic T cells involved in ATLL commonly express CD3, CD4, CD25, CD30, and programmed death 1, and T-cell clonality frequently is present.11,22 Even with staining, diagnosis of ATLL is difficult, as it requires positive testing for HTLV-1 antibody as well as monoclonal integration of HTLV-1 proviral DNA into tumor cells.11 Clinical information is vital in coming to this diagnosis, as there is such great histopathologic overlap with other cutaneous T-cell lymphomas.23
Differential Diagnosis
The differential diagnosis includes other small- or medium-sized T-cell lymphomas. The chronic and smoldering types can be difficult to distinguish from mycosis fungoides. Primary cutaneous CD4+ small- or medium-sized pleomorphic T-cell lymphoma also must be considered, though it often is confined to the skin and can be differentiated from ATLL, as systemic involvement is commonly present in the latter.
Treatment
Treatment decisions should be made based on the subclassification and prognostic factors at the time of diagnosis. High doses of interferon alfa and zidovudine may show some benefit, but many cases require multiagent chemotherapy.22 The only possible curative treatment is allogeneic stem cell transplant. Mogamulizumab, an antichemokine receptor 4 monoclonal antibody, has demonstrated some ATLL antitumor activity.24