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Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an uncommon lymphoproliferative disorder of mature [CD4.sup.+] T cells that is caused by the retrovirus human T-lymphotrophic virus type 1 (HTLV-1). (1) Adult T-cell leukemia was originally described by Takatsuki et al in 1977. HTLV-1 was discovered independently in Japan and the United States. Seroepidemiologic studies in HTLV-1 endemic areas further established the relationship between HTLV-1 and ATLL. (1) This review will discuss the epidemiology, clinical manifestations, pathogenesis, microscopic features, ancillary studies, prognosis, and treatment of ATLL.

EPIDEMIOLOGY

Presently, about 20 million people worldwide are HTLV-1 carriers, and most infected individuals reside in endemic areas which include southern Japan, Africa, the Caribbean basin, and Latin America. The prevalence rate of HTLV-1 in Japan ranges from 0% to 37% depending on geographic area; in the United States and Europe it is less than 1% and is primarily seen in immigrants from endemic countries. (2) The lifelong viral carrier state and long latency (20-40 years) exist after HTLV-1 infection; therefore, the lymphoma is exclusively found in the adult population and is extremely rare in children (<25 cases reported). (2-4) The lifetime risk of progression to ATLL in an HTLV-1-positive patient is 2.1% for women and 6.6% for men. (5) The mean age of onset is 60 years (range, 20-80 years), with a slight male predilection (male to female ratio, 1.5:1). * The overwhelming majority of ATLL cases occur in patients infected during the early years of life, presumably because of a less efficient immune response in this age group: in addition, the prolonged infection may increase chances of accruing subsequent mutations, and ultimately malignant transformation. (6)

Major paths of viral transmission are breast feeding, blood exposure, and unprotected sex. The viral transmission rate from infected mother to child is approximately 20% and depends on HTLV-1 previral load, period of breast feeding, and maternal-fetal concordant human leukocyte antigen (HLA) class I type. (2,7) Exposure to infected blood is the most efficient mode of HTLV-1 transmission; risk of infection after transfusion from an HTLV-1-seropositive donor is 15% to 60%. (2,7) Among blood products, a packed red blood cell transfusion carries the highest risk, whereas blood plasma and cold storage of blood have a lower risk of transmission, probably because of the death of HTLV-1-infected lymphocytes. Interestingly, breast feeding is more correlated with ATLL, and blood transfusion is more correlated with HTLV-1-associated myelopathy/tropical spastic paraparesis. (2) A few cases of donor-derived stem cell transplantation resulting in ATLL have also been reported. (8) HTLV-1 transference due to sexual intercourse is more frequent from male to female than from female to male. (7)

Individuals with HLA alleles A26, B4002, B4006, and B4801 appear to be genetically more predisposed to develop ATLL. (1) Family studies have shown a very strong association among HTLV-1 infection in mothers of patients with ATLL compared with mothers of asymptomatic carriers or HTLV1-associated myelopathy. (9) Adult T-cell leukemia/lymphoma is significantly greater in patients simultaneously infected by HTLV-1 and Strongyloid.es stercoralis, or those infected with HTLV-1-associated infective dermatitis. (6)

CLINICAL FINDINGS

The World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues in 2008 subclassified ATLL into 4 distinct variants according to the Shimoyama classification: acute (60%), lymphomatous (20%), chronic (15%), and smoldering (5%). (1) There are no sine qua non features for each variant, and overlap is seen.

The acute variant manifests as marked leukocytosis with atypical lymphocytes and eosinophilia. Hypercalcemia with or without osteolytic lesions is present in more than 70% of patients, which may result in renal dysfunction and neuropsychiatric disturbances. Elevated lactate dehydrogenase level is not uncommon. Patients present with constitutional symptoms, massive lymphadenopathy sparing mediastinum, cutaneous lesions, and organomegaly. (10,11) Central nervous system involvement in ATLL ranges from 0% to 25%; imaging studies are identical to those for other primary central nervous system lymphomas, characterized by multiple ring-enhancing lesions. These lesions are mostly asymptomatic and are seen more frequently in acute and lymphomatous variants, essentially during relapse or systemic ATLL. (12) Respiratory complications are more frequent in acute ATLL secondary to tumor cell infiltration or opportunistic infections, such as cytomegalovirus, Pneumocystis jiroveci pneumonia, toxoplasmosis, and bacterial abscess or sepsis. (10,13) The lymphomatous variant is an aggressive advanced disease resembling acute-onset subtype. Marked lymphadenopathy without leukemia is a prominent feature. Skin involvement and hypercalcemia are less frequent. (1) The chronic variant typically presents with skin rash, leukocytosis with absolute lymphocytosis, mild lymphadenopathy, and hypercalcemia. (1,5) The smoldering variant is asymptomatic and is characterized by normal white blood cell count with less than 5% circulating atypical lymphoid cells and without associated hypercalcemia or organomegaly. (1) Skin and pulmonary involvement is common. Progression to acute variant can occur. The cutaneous variant presents with skin lesions without systemic involvement. (14)

Acute ATLL is the most common subtype in children among the reported cases, followed by the smoldering and chronic variants. Most common organ involvement in children is skin, followed by lymph nodes, liver, and spleen. (4)

PATHOGENESIS

HTLV-1 was the first human retrovirus to be identified. (15) Within infected cells, the single-stranded RNA virus is converted to proviral DNA and then integrated into host DNA by viral integrase. (2) Whether HTLV-1 integrates into [CD4.sup.+] T cells or hematopoietic progenitor stem cells in infants is not currently well established. (3,16) However, recent studies show that hematopoietic progenitor stem cells play a major part in the initiation of tumorigenesis and also serve as a viral reservoir. The latter function helps HTLV-1 evade the host immune response and ultimately results in long survival and latency. (3)

Transformation of HTLV-1-infected cells to ATLL depends on numerous factors, of which the most important are host immune status and viral-encoded genes. Two HTLV-1 transactivator x (Tax) protein and HTLV-1 basic leucine zipper factor (HBZ), appear to play a central role. (6,16-19) Tax protein is a transactivator of viral RNA and also has a profound role in immortalization through multiple mechanisms. (6,17) HTLV infection is considered to be a 2-phase process. The initial phase is Tax mediated, characterized by production of 500 to 5000 clones of T cells in an infected host. Once immunity develops, [CD8.sup.+] cell-mediated cytotoxic T lymphocytes can eliminate the host Tax-expressing cells, thus containing the infection. The maintenance phase follows, with low immunogenicity and clonal expansion of infected cells mainly driven by HBZ. (6,16,19) This is consistent with the observation that Tax expression is depleted and HBZ is persistently detectable in ATLL. (6,16,19)

HTLV-1 can infect different cell types, including T cells, B cells, fibroblasts, dendritic cells, and macrophages. However, regulatory T cells expressing CD25 and transcription factor forkhead box P3 (FOXP3) are considered to be the cell type that transforms to ATLL. (16,20) Regulatory T cells control and suppress the cytotoxic T-lymphocyte function: therefore, HTLV-1-infected regulatory T cells have a survival advantage over other HTLV-1-infected cells that are supposed to be eradicated by cytotoxic T lymphocytes. As a result, there is a profound increase in these cells over a period of time, as seen in ATLL. (16,20) HTLV-1 is proposed to induce and maintain high levels of FOXP3 through chemokine CCL22 expression. (20)

MORPHOLOGY

Peripheral Blood

Anemia, thrombocytopenia, and leukocytosis with neutrophilia and eosinophilia are variably present. Peripheral blood smear demonstrates predominantly "flower cells," which are medium- to large-sized lymphocytes with petallike nuclei, coarse chromatin, and inconspicuous nucleoli (Figure 1). However, a few blasts or immunoblast-like cells may be noted. (5) Peripheral blood involvement is not detected in the lymphomatous and smoldering variants. (5)

Lymph Node

Lymph nodes in ATLL exhibit indistinct and heterogeneous morphology, which requires immunologic and viral studies to make a definitive diagnosis. Lymph node involvement is usually diffuse, with primarily paracortical expansion (Figure 2, A). Histologic types include: (1) Hodgkin-like, characterized by Reed-Sternberg-like cells histologically and immunophenotypically in a background of clonal T cells; (2) pleomorphic (medium and large cell) type, having, as the name indicates, giant T cells with irregular nuclear contours; (3) pleomorphic small cell type, containing neoplastic T lymphocytes that resemble normal lymphocytes but have irregular nuclear borders; (4) anaplastic large cell lymphoma (ALCL) type, variant, which is characterized by large, bizarre cells with generous amounts of cytoplasm and prominent nucleoli, with or without multinucleated giant cells (Figure 2, B and C); and (5) angioimmunoblastic T-cell lymphoma type, which is the least common and is defined by the presence of clear lymphoma cells with inflammatory infiltrate and high endothelial venules in the background. (5,21)

Patients with Hodgkin-like and pleomorphic small cell types have better survival compared with ALCL and angioimmunoblastic lymphoma type. (21)

Bone Marrow

Bone marrow biopsy is not imperative for diagnosis or subclassification. It is variably involved in the acute variant. There may be subtle or patchy infiltrate of atypical lymphoid cells with irregular nuclear contours. The pattern of involvement is either diffuse or interstitial, with or without accompanying fibrosis. Increased osteoclasts resulting in bone resorption and hypercalcemia are a prominent feature in some individuals. (5,21) Bone marrow involvement (>5% of ATLL cells on a bone marrow aspirate or biopsy) is considered an independent poor prognostic factor; a patient with ATLL should be examined for possible involvement. (22,23)

Skin Manifestations

Cutaneous lesions in all clinical variants of ATLL have been described and range from 43% to 72%.21 Clinically, skin lesions may include patch, plaque, multipapular, nodulotumoral, erythrodermic, and purpuric lesions. (24) All erythrodermic lesions are seen in the acute variant, whereas the patch-type lesions are predominantly noted in the smoldering subtype. (24) Histopathologically, 3 different patterns of infiltration are seen: perivascular, nodular, and diffuse. (21) Presence of epidermotropism and Pautrier microabscess is not uncommon. (5) Because of nonspecific findings and a resemblance to other cutaneous T-cell lymphomas, the differential diagnosis can be challenging on histology and requires the use of HTLV-1 antibodies to HTLV-1 provirus DNA in tumor cells to label ATLL-associated skin lesions. (25)

IMMUNOHISTOCHEMISTRY

The ATLL cells express mature T-cell markers, like CD2, CD5, CD25 (strong and uniform), CD29, CD45RO, TCR (ab), and HLA-DR; these commonly express CD4 and are negative for CD8. There is aberrant loss of CD7 and often downregulation of CD3. (5,23) Studies have shown that lymphoma cells show variable expression of regulatory Tcell phenotype characterized by [CD4.sup.+]/[CD25.sup.+] (83%; Figure 3); FOXP3+ (36%); CCR4 (95%); and CCR8 (35%). FOXP3 expression is linked more commonly to a clinical immunocompromised state and smaller lymphoma cells, and it is negative in [CD30.sup.+] ALCL type. (26) CD25 expression may be distinctive but not specific, because it is also positive in Pro T lymphocytic leukemia and Seezary syndrome. Adult T-cell leukemias/lymphomas with double-positive T cells ([CD4.sup.+], [CD8.sup.+]) and only [CD8.sup.+] T lymphocytes have also been described; the former are associated with decreased survival, as reported in isolated case reports. (5,23,27,28)

Adult T-cell leukemia/lymphoma cases with [CD30.sup.+] ALCL morphology are anaplastic lymphoma kinase 1 negative. (27) Rarely, cells can be positive for CD15 and may resemble Hodgkin disease. (27) High Ki-67 (proliferation index) is associated with worse outcome. (27)

CYTOGENETICS AND MOLECULAR STUDIES

Karyotype in ATLL is complex and without any characteristic abnormality, particularly in the acute forms. The abnormalities include aneuploidy (+3, +7, +21, -X, -Y), abnormalities of 3p, and translocations involving 14q11 and 14q32 sites of TCR(alpha) and TCR(delta) genes, respectively. (23) FOXP3+ ATLLs have less complex cytogenetic abnormalities compared with [FOXP3.sup.-]. It has been proposed that a complex karyotype is more often seen in ATLL relapse, which is either normal or simple at the time of diagnosis, emphasizing the concept of multistep lymphogenesis in ATLL. (26)

Monoclonal insertion of HTLV-1 provirus DNA is found in virtually all cases of ATLL and is identified by Southern blotting or polymerase chain reaction. (24) Positive HTLV-1 serology with appropriate clinical and morphologic findings of ATLL is sufficient to reach a diagnosis. HTLV-1 molecular testing should be performed in a seronegative patient with a high suspicion of ATLL. (5,23)

Mutations or deletions of tumor suppressor genes CDKN2A (p16), CDK2B (p15), and TP53 (p53) are reported in approximately 50% of ATLL patients, and this finding may direct therapy in the future. (5,23)

DIFFERENTIAL DIAGNOSIS

The main differential diagnosis of ATLL includes peripheral T-cell lymphoma not otherwise specified, ALCL, mycosis fungoides/Sezary syndrome, and angioimmunoblastic T-cell lymphoma. (5,29)

Peripheral T-cell lymphoma not otherwise specified is the most frequent type of peripheral T-cell lymphoma, comprising 29.5% of peripheral T-cell lymphoma. This subgroup contains all the cases that have no clear and accepted criteria for one of the specific types in the World Health Organization classification. The clinical history and HTLV1 status by serology or molecular testing is pivotal in differentiating ATLL from peripheral T-cell lymphoma not otherwise specified. (30)

Anaplastic large cell lymphoma can be indistinguishable from ATLL because of a significant overlap in morphology and immunohistochemical studies. Tumor cells are positive for CD30 in ATLL and ALCL; however, the latter show strong membranous and Golgi staining in almost every cell. Anaplastic lymphoma kinase staining and expression of cytotoxic granule-associated protein in addition to HTLV-1-negative serology are helpful in making a correct diagnosis of ALCL. (31)

Angioimmunoblastic T-cell lymphoma represents 16% of T-cell lymphomas in North America and is an important differential diagnosis of ATLL, considering both can have hypercalcemia, diffuse lymphadenopathy, and skin involvement. (29) Angioimmunoblastic T-cell lymphoma displays high endothelial venules and neoplastic cells with clear cytoplasm expressing CD10 and CXCL13 and with an irregular meshwork of expanded [CD21.sup.+] dendritic cells. (32,33) Presence of HTLV-1 proviral integration in tumor cells detected by molecular studies favor ATLL over angioimmunoblastic T-cell lymphoma. (33)

Mycosis fungoides/Sezary syndrome can mimic ATLL with cutaneous involvement because both lesions can depict atypical neoplastic cells with epidermotropism and Pautrier abscess. HTLV-1 serology or confirmation of viral integration in neoplastic cells will favor ATLL. (34)

PROGNOSIS AND TREATMENT

For clinical purposes, ATLL has been divided into 2 groups: indolent (smoldering and chronic variants) and aggressive (acute and lymphomatous variants). (11) The projected median survival times for different variants are smoldering, 2 years; chronic, approximately 2 years; lymphomatous, 10 months; and acute, 6 months. (1)

Adult T-cell leukemia/lymphoma with primary skin lesions without systemic involvement has better prognosis compared with cases with secondary skin involvement. (25) Erythrodermic-type cutaneous lesions have a shorter survival time, followed by the nodulotumoral and multipapular types. The patch and plaque types are linked to better outcomes. Lymphoma cells expressing CCR4 are associated with skin involvement and bad prognosis. (25) Smoldering type associated with nodulotumoral-type skin lesions has a worse prognosis compared with smoldering type without skin lesions. (24)

Additional poor prognostic indicators include age older than 40 years, advanced performance status (2 or more grade) with performance status (PS) based on the 5-grade scale of the World Health Organization, hypercalcemia, high blood lactate dehydrogenase level, [[beta].sub.2]-micro globulin, high serum CD25 levels, more than 3 extranodal lesions, liver and spleen enlargement, lymphadenopathy, and expression of drug-resistance protein and lung-resistance protein. (18,23,24) Proviral load may affect prognosis in ATLL and serve as a marker of tumor burden in diagnosed ATLL. (18)

Indolent ATLLs are usually not treated, because they have a relatively better prognosis and because many of the patients are either too old or have additional systemic diseases at presentation. The primary treatment option currently considered is watchful waiting. Recent studies have shown excellent survival with zidovudine/interferon-[alpha] treatment in patients with indolent ATLL, but its efficacy needs confirmation. For aggressive ATLL, multidrug chemotherapy and/or allogenic stem cell transplantation is the treatment modality in Japan. In Western countries, zidovudine/interferon-[alpha] with or without chemotherapy is the treatment of choice. Comparative studies are needed to determine the relative efficacy of treatment options. In spite of the present treatment options, the outcome of aggressive ATLL remains dismal. (10,11)

CONCLUSION

Adult T-cell leukemia/lymphoma is a malignant lymphoproliferative neoplasm of mature T cells caused by HTLV-1, with characteristic clinicopathologic features. In spite of a greater understanding of the pathogenesis of ATLL, optimal treatment is yet to be determined and overall prognosis remains dismal.

The authors would like to thank Jeffrey R. Jacobsen, MD, director of immunopathology at St Jude Children's Research Hospital, for his assistance.

Please Note: Illustration(s) are not available due to copyright restrictions.

References

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Sohail Qayyum, MD; John K. Choi, MD, PhD

Accepted for publication April 2, 2013.

From the Department of Pathology, University of Tennessee Health Science Center, Memphis (Dr Qayyum); and the Department of Hematopathology, St Jude Children's Research Hospital, Memphis, Tennessee (Dr Choi).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Sohail Qayyum, MD, Department of Pathology, University of Tennessee Health Science Center, 930 Madison Ave, 5th Floor, Memphis, TN 38163 (e-mail: sohailqayyum@gmail.com).

Caption: Figure 1. Peripheral blood smear from a 21-year-old man with adult T-cell leukemia/lymphoma showing "flower cell" (Wright-Giemsa, original magnification XI000).

Caption: Figure 2. A, Low-power view of a lymph node from a 21-year-old man with adult T-cell leukemia/lymphoma showing effaced architecture by diffuse sheets of moderately polymorphous mononuclear cells. B, The same specimen at higher magnification demonstrating the numerous mitotic figures and extensive apoptotic debris; neoplastic cells are intermediate in size with moderate amounts of eosinophilic cytoplasm, irregular cleaved and angular nuclear contours, coarse chromatin, and variably prominent nucleoli. C, There are scattered large neoplastic cells with horseshoe-shaped nuclei (hematoxylin-eosin, original magnifications X100 [A], X400 [B], and X1000 [C]).

Caption: Figure 3. Lymphoma cells are strongly [CD4.sup.+] (A) and [CD25.sup.+] (B) (immunohistochemistry, original magnifications x100).
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Date:Feb 1, 2014
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