Adult T-Cell Leukemia/Lymphoma
Melissa Pulitzer
DEFINITION
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell malignancy of a mature helper-T/regulatory-phenotype, which develops after chronic infection with human T-lymphotropic virus 1 (HTLV-1). The cells usually express CD4 and the IL-2 receptor CD25. Malignant T-cells in ATLL may present primarily in the skin or systemically with secondary skin involvement. Classification of ATLL as leukemia or lymphoma depends on the presentation as either infiltration of the blood by neoplastic cells, or as infiltrative disease of the lymphoid organs, respectively.1
EPIDEMIOLOGY
ATLL most often occurs in patients from areas endemic for HTLV-1, with a median age of 57 years in patients of Japanese origin,2 and of 53 years in Caribbean patients,3,4 and has a slight predilection for males (1.5:1).5 HTLV-1 affects 15 to 20 million people worldwide, mostly as a subclinical infection in endemic areas such as southwest Japan, the Caribbean basin, South and Central America, equatorial Africa, Melanesia, and in small groups in the Middle East. Transmission of HTLV-1 is most often vertical (mother to child via breast milk). Other means of transmission include sexual intercourse and blood transfusion of packed red blood cells. Antibodies to HTLV-1 are found in 6% to 37% of healthy adults aged over 40 in endemic areas in Japan and are increasing in nonendemic areas in Japan and the United States, suggesting spread by move of carriers.6 The current seroprevalence of HTLV-1 in the United States is reportedly 0.01% to 0.03%.5
Up to 5% of HTLV-1 carriers will develop ATLL, usually after a latency of two to four decades following infection early in life. Earlier exposure to virus is associated with a higher risk of malignancy. Overall lifetime risk of progression to ATLL is 2.1% in women and 6.6% in men.7 The incidence of ATLL is approximately one per million individuals in the United States per year (300 per year, with an age-adjusted incidence of 0.05 in males, and 0.03 in females per 100,000 per year).8
ETIOLOGY
ATLL was described as a clinical entity in Japan in 1977 by Uchiyama, Takatsuki, and others.9,10 Shortly thereafter, retrovirus particles that were later identified as HTLV-1 were isolated from a patient with cutaneous T-cell lymphoma in the United States,11 resulting in the confirmation of the Japanese syndrome as a virally-associated lymphoproliferative disease.
HTLV-1 is a single-stranded RNA virus with a diploid genome, which infects human CD4+ helper T cells, undergoes reverse transcription to proviral DNA, and randomly integrates into the host genome. Early in infection, HTLV-1 is thought to spread via cell-to-cell conjugation, viral budding, and the formation of an extracellular viral assembly, which can easily transmit to adjacent immune cells.12 Over time, viral burden increases as the virus induces clonal proliferations of infected cells in most HTLV-1 carriers. Clones each exhibit a different integration site of provirus, and can persist for decades. Insertion of provirus into cellular genomic DNA near transcriptional start sites of cellular genes,13 or near activating epigenetic markers, may confer a survival advantage for those clones, influencing the number of clones expressed.14,15 Over time, the high relative abundance of a clone of cells with a single viral integration site constitutes “monoclonality,” correlating with neoplasia. Although no specific viral integration hot spots have been identified, some genes are more frequently affected than others (Table 23-1).15
TABLE 23-1 Genes Harboring Provirus15 | ||||||||||||
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The provirus itself encodes products, which promote cellular transformation, including the retroviral long terminal repeats gag, pol, env, and a unique pX region. The latter encodes a 40-kDa cell-transforming oncoprotein Tax and human basic zipper factor HBZ, which are implicated in proliferation. The resultant HTLV-1 proteins are often silenced in both HTLV-1 carriers and ATLL patients, allowing infected cells to evade the host response16 by interactions with the host microenvironment17 or by other epigenetic mechanisms.18
CLINICAL PRESENTATION AND PROGNOSIS
Although as many as 31% of patients may present with disease limited to the skin,4 more commonly there is systemic involvement at presentation. This includes widespread lymph node and marrow or other extranodal (lung, liver, GI) involvement, elevated lactate dehydrogenase (LDH) and/or hypercalcemia, with or without skin lesions. Eventually, skin involvement develops in ∼50% of all patients. Peripheral blood may show anemia, thrombocytopenia, leukocytosis, neutrophilia, and/or eosinophilia. Flower cells (Fig. 23-1) or occasional blasts may be present. Some of these findings may vary according to geographic region, for example, less hypercalcemia and concomitantly less osteolysis have been identified in Caribbean patients.4
 FIGURE 23-1. A classic “flower cell” of adult T-cell leukemia, showing multilobated nuclei, in a background of atypical monolobated lymphocytes and erythrocytes from a peripheral smear. (Photo courtesy of Mikhail Roshal, MD.) |
The spectrum of ATLL presentations was originally delineated by the Shimoyama classification, which divides ATLL presentations into acute, chronic, lymphomatous, and smoldering types19,20 (Table 23-2). Over time, the acute and lymphomatous forms have come to be known as the most aggressive forms of the disease, and the chronic and smoldering forms are less aggressive. Patients with a smoldering form can sometimes progress to a more aggressive type of ATLL. Not only do the chronic and smoldering subtypes have a more protracted course, but they also show more frequent skin involvement (43% to 72%).21 When the skin is the only organ involved, the prognosis tends to be better.22 There is controversy as to whether skin involvement in patients with extracutaneous disease is a poor prognostic factor, with some authors finding an adverse impact of skin involvement,23 and others finding no survival difference.
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Among patients with skin involvement, smoldering ATLL with a deep versus superficial infiltrate may have a worse overall survival.23 Moreover, the type of clinical skin eruption in smoldering ATLL has been shown to be an independent prognostic factor (Table 23-3). Patch and plaque disease were linked to better outcomes; erythrodermic presentations correlated with shorter survival (present in typically acute ATLL); and smoldering ATLL with nodulotumoral lesions was worse than smoldering ATLL without skin lesions,24 although smoldering disease was the variant most commonly marked by patch lesions.25 An alternate designation for this former type of smoldering ATLL was suggested as “lymphoma type of ATLL, extranodal primary cutaneous variant.”26 Extranodal primary cutaneous ATLL with no leukemic component has been subdivided into erythematous-papular and tumoral types.27,28 Worse outcomes were identified for primary cutaneous ATLL compared to smoldering ATLL overall and a worse outcome for the tumoral versus erythemopapular type was specifically identified. “Primary cutaneous tumoral type” has been proposed by some as a fifth clinical type in the Shimoyama classification.28
TABLE 23-3 Clinical Lesion Stratification for Adult T-Cell Leukemia/Lymphoma24 | ||||||||||||||||
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Beyond the common nodules, tumors, papules, plaques, and macules25 of ATLL (Fig. 23-2), clinical presentations also include subcutaneous tumors, erythroderma, purpura, alopecia, and folliculitis (Fig. 23-3). Although all types can mimic other cutaneous lymphomas, the clinical differential diagnoses also include a wide range of nonlymphomatous entities.4
 FIGURE 23-2. Plaques and tumors in a patient with ATLL, mimicking MF. |
 FIGURE 23-3. Follicular papules in a patient with folliculitis-like ATLL. |
Patients with all subtypes of ATLL are susceptible to superimposed infection owing to impaired cellular immunity. Such infections range from tuberculosis to crusted scabies,9 pneumocystic carinii, fungi, viruses, and parasites. Fungal infections of the skin including tinea and candida are seen in 50% of ATLL patients, are often intractable with treatment, and exhibit little inflammation, consistent with defective innate immunity to these organisms.29 Strongyloides stercoralis is often seen in HTLV-1 patients (16.3% in HTLV-1+ vs. 7.6% in HTLV-1−30).
Initial diagnosis of ATLL is made by clinical presentation and confirmation of HTLV-1 seropositivity. Enzyme-linked immunosorbent assay (ELISA) screening is the test most commonly used for diagnosis of HTLV-1.28 If positive, serum is tested by immunoblot assay (typically Western blot) for confirmation. If cases are indeterminate by ELISA/blot sequence, then polymerase chain reaction (PCR) is used to look for proviral DNA in peripheral blood mononuclear cells (PBMCs). Predictors of the evolution of clinical disease include rising or high proviral load (PVL), (typically rising over decades from <0.001% to >100%). The risk of disease is increased with PVL >4% in Japan or >10% in the United Kingdom.31 Another major determinant of risk may be the absolute number of clones,15 which is determined by the efficiency of host cytotoxic T-lymphocyte (CTL) response to virus.32,33
Regarding therapies, clinically aggressive subtypes (acute, lymphoma, and unfavorable chronic) are managed as subtypes of aggressive non-Hodgkin lymphoma, often with allogeneic stem cell transplant, whereas indolent types (favorable chronic and smoldering) are treated similar to CLL,34,35,36 often with watchful waiting. Skin lesions of indolent ATLL can sometimes be treated by topical steroids, UV light, radiation, systemic steroids, oral retinoids, interferon, or single-agent chemotherapy.37
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