Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma

INTRODUCTION — Adult T cell leukemia-lymphoma (ATL) is a mature T cell malignancy that generally presents with widespread involvement of lymph nodes, peripheral blood, and/or skin [1]. Although ATL is often highly aggressive, the clinical presentation is variable and, in some cases, it is an indolent disorder. ATL is caused by chronic infection with the human T-lymphotropic virus, type I (HTLV-I).

This topic discusses the epidemiology, pathogenesis, clinical presentation, pathologic findings, and diagnosis of ATL.

Treatment of ATL is discussed separately. (See "Treatment and prognosis of adult T cell leukemia-lymphoma".)

EPIDEMIOLOGY — ATL is an uncommon lymphoid neoplasm that occurs in patients with human T-lymphotropic virus, type I (HTLV-I) infection. Incidence varies by population according to the prevalence of HTLV-I infection [2]. Infection with HTLV-1 is endemic in several islands in southwestern Japan, the Caribbean basin (eg, Jamaica and Trinidad), western Africa, Peru, northeast Iran, and the southeastern portion of the United States; most affected patients live in or originate from these areas [3-9].

In the United States as a whole, the incidence of ATL is approximately 0.05 cases per 100,000 people [10]. ATL is more common in Black Americans and Asian/Pacific Islanders than White Americans and there is a slight male predominance overall [11]. The median age at diagnosis is in the sixth decade [2,12]. However, median age at diagnosis can vary with geographic location. As an example, a study of 126 patients with ATL from Jamaica reported a median age of 43 years [13].

Since ATL is associated with HTLV-I infection, patients with ATL are also at risk for HTLV-I-associated myelopathy, also known as tropical spastic paraparesis. HTLV-I-associated myelopathy is discussed in more detail separately. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)

PATHOGENESIS — ATL is uniformly associated with human T-lymphotropic virus type I (HTLV-I) infection of CD4-positive T cells, the cell of origin for the tumor [14]; this infection is thought to play a significant role in the pathogenesis of ATL. In xenograft models, the tumor-initiating cell appears to be an HTLV-I infected CD4-positive memory T cell with stem cell-like properties [15]. All of the malignant cells in a particular tumor share the same HTLV-I proviral genomic integration site. Since proviral integration is believed to occur in a more or less random fashion, the clonal nature of proviral integration sites in tumors indicates that viral infection and integration must occur prior to malignant transformation and clonal expansion. It is unclear whether the particular insertion location affects the phenotype of the cell (eg, by dysregulating nearby genes).

It is estimated that there are 5 to 10 million HTLV-1 carriers worldwide [16]. The long-term risk of developing ATL following infection with HTLV-I in endemic areas has been estimated to be 4 to 5 percent, usually after a latency period of several decades [17,18]. Exposure to the virus early in life increases the risk of eventual development of ATL. A shorter latency period has been noted in infected patients receiving treatment with immunosuppressive agents for other conditions [19-21]. The low incidence of ATL in HTLV-I infected individuals and the long latency period between HTLV-I infection and ATL development indicate that infection with HTLV-I alone is insufficient for malignant transformation [14,22]. It has been reported that clones of ATL cells with the same proviral integration site can have different T cell receptor rearrangements, raising the possibility that ATL may arise from immature HTLV-1 infected hematopoietic progenitors [23].

The exact mechanism by which HTLV-I contributes to tumor development is unknown. One suspect is the tax oncoprotein (the gene product of the viral gene tax [transactivating gene of the X region]) induces cellular proliferation, promotes cellular survival, and impairs DNA damage repair mechanisms [24,25]. Tax protein activates gene expression by acting on host transcription factors such as nuclear factor-kappa-B (NF-kB); tax protein results in migration of NF-kB from the cytoplasm to the nucleus where it activates genes responsible for cellular proliferation. In addition, tumor survival is promoted by the constitutive activation of the JAK-STAT pathway [26,27] and by the inactivation of the tumor suppressor TP53 [28].

Somatic mutations collaborate with HTLV-1 infection to cause lymphomagenesis. Mutations in RHOA, which encodes a GTP-binding protein, and TET2, an epigenetic regulator, are found in a subset of ATL cases [29]. RHOA and TET2 mutations are also seen in other subtypes of peripheral T cell tumors (eg, angioimmunoblastic lymphoma). Although their functional contributions to ATL remain to be ascertained, work in other peripheral T cell lymphoma models has shown that mutated RHOA promotes lymphomagenesis, possibly by augmenting PI3K/AKT signaling downstream of ICOS, a T cell costimulatory protein [30]. Whole exome sequencing of 81 cases of ATL identified 50 genes that were recurrently mutated, including 13 genes that were mutated in more than 10 percent of the cases [31]. The most frequently mutated genes included PLCG1 (36 percent), PRKCB (33 percent), CARD11 (24 percent), VAV1 (18 percent), and IRF4 (14 percent), all of which are involved in signaling downstream of the T cell receptor and lead to activation of NF-kB. This same study noted that ATL cells often acquire copy number variants, some involving regions containing the genes cited above. Whole-genome sequencing of 150 cases uncovered additional acquired genetic events associated with ATL [32]. One-third of cases had loss-of-function mutations targeting the long isoform of CIC, a transcriptional repressor, while another 13 percent had gain-of-function mutations in REL, a gene encoding a member of the NF-kB transcription factor family. Other frequently affected genes include TP53, which is mutated in 10 to 50 percent of ATL [33,34]; and RB1, which is usually unmutated but may be suppressed through other mechanisms [35,36]. Finally, ATL is one of a number of cancers in which structural aberrations have been reported to lead to overexpression of the immune checkpoint protein PD-L1 [37], possibly pointing to an important role for immuno-evasion in its development and progression.

As described below, ATL is frequently associated with hypercalcemia, which can be severe. The hypercalcemia seen in ATL is paraneoplastic in origin and thought to arise from cytokines liberated from the malignant cells. (See "Hypercalcemia of malignancy: Mechanisms".)

The following mechanisms have been proposed as causes of hypercalcemia:

●Constitutive production of parathyroid hormone related protein (PTH-RP) [38-40]

●Tumor necrosis factor-beta [41] or interleukin-1 [42]

●Increased expression of RANKL (receptor activator of nuclear factor kB ligand) [43]

These factors may also contribute to the genesis of the lytic bone lesions, increased bone turnover, increased serum alkaline phosphatase, and the "super scan" of the skeleton seen on radionuclide imaging [44,45].

CLINICAL FEATURES — The clinical features of ATL include evidence of generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, hypercalcemia, lytic bone lesions, and skin lesions. The frequency of these differs among patient groups and has been the basis on which clinical variants have been defined.

Clinical variants — Several clinical variants of ATL have been described: acute, lymphomatous, chronic, and smoldering; these appear to have differing genomic alterations and different clinical courses [46,47]. Progression from chronic and smoldering disease to aggressive disease resembling the acute variant eventually occurs in up to 25 percent of cases, and may be associated with specific changes on gene expression profiling [48].

Acute — The most common presentation of ATL, occurring in about 60 percent of cases, is the acute variant, which has a generally poor prognosis with survival measured in months to a year despite aggressive treatment [47,49]. (See "Treatment and prognosis of adult T cell leukemia-lymphoma".)

Patients with the acute variant of ATL most frequently present with systemic symptoms, organomegaly, lymphadenopathy, an elevated lactate dehydrogenase (LDH) level, and circulating malignant cells. The white blood cell (WBC) count is usually elevated and may be higher than 100,000/microL.

Common presenting signs or symptoms include [44,47,50-52]:

●A high peripheral blood white blood cell count is common due to the presence of circulating lymphocytes with highly abnormal convoluted nuclei (picture 1).

●Bone marrow involvement is observed in 5 to 35 percent of cases.

●Lymphadenopathy is seen in almost all cases.

●Involvement of the liver and spleen is present in approximately 16 and 22 percent, respectively.

●40 to 50 percent will have hypercalcemia with or without lytic bone lesions at presentation and an additional third will develop hypercalcemia at some point during the course of their disease.

●Approximately 25 percent will have skin lesions at diagnosis, often simulating those seen in mycosis fungoides. Skin lesions may be patches (7 percent), plaques (27 percent), papules (19 percent), tumors (39 percent), erythrodermic lesions (4 percent), and purpuric lesions (4 percent) [53]. The prognosis may vary with different types of skin lesions being better for those with patches or plaques and worst for patients with erythrodermic or purpuric lesions.

Less common clinical features may include [54,55]:

●Interstitial pulmonary infiltrates, which may be due to pneumocystis jirovecii pneumonia

●Central nervous system involvement with mass lesions on imaging

Lymphomatous — The lymphomatous variant accounts for approximately 20 percent of cases and is characterized by prominent lymphadenopathy without blood involvement. Patients frequently have an elevated LDH level and can have hypercalcemia. Prognosis is poor with a survival similar to that of patients with the acute variant.

Chronic — Approximately 10 percent of cases are a chronic variant. These patients present with skin lesions, mild lymphadenopathy, leukocytosis, and an absolute lymphocytosis that may be stable for months to years [56]. Median survival is two to five years, however, there is a subgroup of patients with unfavorable chronic-type ATL, which is defined by a low serum albumin, high LDH, or high blood urea nitrogen concentration. These patients have a poor prognosis similar to that of the acute and lymphoma variants.

Smoldering — The smoldering variant is least common, accounting for approximately 10 percent of cases. These patients are often asymptomatic except for skin and/or pulmonary lesions. They have normal blood lymphocyte counts with <5 percent circulating neoplastic cells and normal calcium levels. Median survival without treatment is approximately three years [56].

Primary cutaneous tumoral — Primary cutaneous tumoral (PCT) ATL is a distinct subtype with cutaneous lesions that appear as rapidly growing tumors; it is a provisional subtype of ATL, according to a consensus meeting report [57]. The cutaneous manifestations are primarily nodulo-tumoral and pathologic findings reveal a pleomorphic high-grade T cell lymphoma with medium or large cells, prominent perivascular infiltration, and scant epidermotropism [58]. PCT-ATL is generally less aggressive than acute or lymphoma types, but it is more aggressive than chronic/smoldering type. It must be distinguished from other cutaneous T cell lymphomas, such as mycosis fungoides and peripheral T cell lymphoma.

Hypercalcemia and lytic bone lesions — As mentioned above, the frequency of hypercalcemia and lytic bone lesions differs among the variants of ATL. In the acute variant, approximately 70 percent of patients with ATL will have hypercalcemia at some point in their disease course while 40 percent will have lytic bone lesions [59]. Hypercalcemia can be severe with calcium levels as high as 21 mg/dL (5.25 mmol/liter). Signs and symptoms related to hypercalcemia such as renal dysfunction or neuropsychiatric disturbances may be prominent among the presenting clinical features. The clinical manifestations of hypercalcemia are discussed in more detail separately. (See "Clinical manifestations of hypercalcemia".)

Immunosuppression — Patients with ATL are immunosuppressed and at risk of developing opportunistic infections including pneumocystis jirovecii pneumonia, cryptococcus meningitis, and disseminated herpes zoster [60]. Severe, and often fatal, infestation by disseminated Strongyloides stercoralis is common as well. (See "Strongyloidiasis".)

A retrospective analysis of 818 patients with ATL found that 213 (26 percent) had infectious complications at the time of diagnosis [61]. Infectious complications were more common in patients with the acute, chronic, or smoldering variants than in patients with the lymphomatous variant. Of the 465 patients with acute variant ATL, the following infections were found at diagnosis:

●Bacterial (mostly pneumonia) in 55 patients (12 percent)

●Fungal (mostly cutaneous) in 38 patients (8 percent)

●Protozoal (mostly strongyloidiasis) in 22 patients (5 percent)

●Viral (mostly herpes zoster) in 13 patients (3 percent)

●339 patients were without infection at diagnosis (73 percent)

PATHOLOGY

Morphology — The morphology of the tumor cells is quite variable from case to case, and a high index of suspicion on clinicopathologic grounds is helpful in arriving at an expeditious diagnosis. The organs involved vary, but can include the peripheral blood and bone marrow, lymph nodes, and skin.

Peripheral blood and bone marrow — The most characteristic morphologic feature of ATL is seen in the peripheral blood of leukemic cases. In such cases, medium sized lymphocytes with condensed chromatin and bizarre hyperlobated nuclei ("clover leaf" or "flower cells") can be found, often resembling the Sézary cells of mycosis fungoides (picture 1) [3]. There is often a small proportion of blast-like cells with deeply basophilic cytoplasm, but not all ATL cells show morphologic atypia; many morphologically normal lymphocytes are leukemic cells. Bone marrow involvement is seen in approximately 35 percent of cases [59]. Bone marrow infiltrates are usually patchy, ranging from sparse to moderate.

Lymph nodes — Involved lymph nodes typically display diffuse architectural effacement, although at early stages of involvement the cells may preferentially accumulate in the T cell areas or sinusoids of the node. A wide range of morphologies may be seen. Most commonly, the neoplastic cells are medium to large-sized with nuclear pleomorphism; the cytoplasm is amphophilic, basophilic, or pale. Reed-Sternberg–like cells and multinucleated giant cells with convoluted or cerebriform nuclei may be present, causing a resemblance to Hodgkin lymphoma [62]. Uncommonly, the tumor can be composed of small-sized lymphoid cells with nuclear pleomorphism, or may resemble anaplastic large cell lymphoma. Mitotic activity is variable. In the background, there is typically a mild to moderate proliferation of high endothelial venules.

Other tissues — On occasion, ATL may present with skin infiltrates similar to those seen in cutaneous T cell lymphoma (mycosis fungoides), with epidermotropism and Pautrier's microabscesses; such cases are more likely to be associated with an indolent course. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

In a study of 71 patients with ATL from Japan, involvement of the stomach was documented by endoscopic biopsy in 21 (30 percent) [63]. The prevalence of infection with Helicobacter pylori was 86 versus 38 percent in those with or without gastric involvement, respectively.

Immunophenotype — The origin of the malignant cell in ATL is a human T-lymphotropic virus, type I (HTLV-I) infected mature CD4+ T-lymphocyte. In a subset of cases, the tumor cells express the transcription factor FoxP3, a marker of immunosuppressive regulatory T cells (Tregs) [64,65]. For purposes of diagnosis, suspected cases should be stained for CD3, CD4, CD7, CD8, and CD25 at a minimum. Tumor cells express T cell associated antigens (CD2, CD4, and CD5), but usually lack CD7 and may exhibit dim CD3 expression. Most cases are CD4+ and CD8- [59]. Rare cases are CD4-/CD8+ or CD4+/CD8+. CD25 is expressed in a majority of the cases [62,66], as is CD52 [49]. Anaplastic large cell variants react with CD30, but are negative for ALK protein and lack rearrangements involving the ALK gene.

Genetics — There is no distinct molecular or karyotypic abnormality in ATL other than clonally integrated HTLV-1, which is observed in all malignant cells [59]. Karyotypic analysis is generally reserved for patients enrolled in clinical trials. The T cell receptor genes are clonally rearranged [67].

The most common karyotypic changes involve copy number alterations of 3q, 6q, and 14q, as well as inv(14) [68]. In three studies, the more clinically aggressive ATL variants had the most complex chromosomal abnormalities [68-70]. Mapping of chromosome 6q in 22 patients with ATL indicated deletions in nine tumors, eight of which shared the same deleted region (6q15-21), a possible site for a tumor-suppressor gene [71].

Deletion of the p16 gene, an important regulator of the cell cycle that is located on chromosome 9p, or reduced production of p16 protein may be associated with a more aggressive clinical course and reduced survival [72,73]. A further description of the p16 gene is presented separately. (See "Inherited susceptibility to melanoma", section on 'CDKN2A gene'.)

Somatic mutations in RHOA, which encodes a GTP-binding protein, and TET2, an epigenetic regulator, are seen in a subset of ATL cases [29], and in other peripheral T cell lymphomas, especially angioimmunoblastic lymphoma. As mentioned earlier, ATL commonly has mutations enhancing T cell receptor signaling that lead to NF-kB activation [31], loss-of-function mutations in TP53 [33,34]; and structural aberrations leading to overexpression of PD-L1 [37] are also common in ATL. (See 'Pathogenesis' above.)

DIAGNOSIS — The diagnosis of ATL is based on a combination of characteristic clinical features, morphologic and immunophenotypic changes of the malignant cells, along with confirmation of human T-lymphotropic virus, type I (HTLV-I) infection [74]. Identification of at least 5 percent tumor cells by cytology and immunophenotype in the peripheral blood with confirmation of HTLV-1 infection is often sufficient to make the diagnosis in patients with acute, chronic, or smoldering type ATL [61]. Patients with lymphomatous lesions should undergo an excisional biopsy of an involved lymph node for histopathologic examination. Testing for clonal proviral integration is not routinely performed, and currently, the diagnosis is usually confirmed by tests for HTLV-1 specific antibodies and/or polymerase chain reaction (PCR)-based tests for the presence of provirus in peripheral blood cells.

●Clinical manifestations – There are no pathognomonic clinical features that clearly distinguish ATL from other disorders. As previously described, a number of clinical variants have been defined. Common features include generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, hypercalcemia, lytic bone lesions, and skin lesions. (See 'Clinical features' above.)

●HTLV-1 infection – Practically all patients with ATL have serologic antibodies to HTLV-I. An enzyme-linked immunosorbent assay (ELISA) is the most frequently used screening test, using antigens prepared from whole virus lysate or by recombinant technology. Western blotting (WB) is normally used for confirmatory testing. WB also distinguishes between infection with HTLV-I and the less pathogenic HTLV-II.

PCR-based testing to detect proviral DNA in tumor cells should be performed in the rare instance where serology is negative but suspicion for ATL is high. This test will also differentiate HTLV-I from HTLV-II infection. Another diagnostic modality is RNA in situ hybridization for the HTLV-1 bZIP transcript (HBS), which appears to be highly sensitive and specific for diagnosing ATL when used on paraffin-embedded tumor samples that are less than two years old [75]. Details on the diagnosis of HTLV-I infection are presented separately. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)

●Histology – As described above, the tumor cell morphology is quite variable. The most characteristic morphologic changes seen in ATL is that of the circulating tumor cells, which are characterized by medium sized lymphocytes with condensed chromatin and bizarre hyperlobated nuclei ("clover leaf" or "flower cells") (picture 1).

●Immunophenotype – The immunophenotype is that of an activated mature T-lymphocyte. The most common immunophenotype is CD4+, CD25+, CD7-, and CD8-.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ATL includes other T cell lymphoid malignancies such as cutaneous T cell lymphoma, T-prolymphocytic leukemia (T-PLL), anaplastic large cell lymphoma, and angioimmunoblastic T cell lymphoma. Some cases of ATL can resemble Hodgkin disease morphologically.

Asymptomatic healthy carriers of HTLV-1 — Flower cells similar to those seen in ATL can be seen in the peripheral blood of asymptomatic healthy carriers of human T-lymphotropic virus, type I (HTLV-1) [76]. Such cases may be difficult to distinguish from smoldering ATL. Southern blotting can be used to identify the clonal integration of HTLV-1 into the circulating cells of smoldering ATL [77], but is no longer available in most centers. An alternative is to use conventional polymerase chain reaction (PCR) testing for T cell receptor gene rearrangements, which can be used to determine if a clonal T cell population is emerging. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology".)

Cutaneous T cell lymphoma — ATL can be difficult to distinguish from forms of cutaneous T cell lymphoma (CTCL), such as mycosis fungoides and Sézary syndrome. Both of these disorders can have cutaneous manifestations with malignant T cells circulating in the peripheral blood and skin biopsy findings that are practically identical morphologically. They can also have a similar immunophenotype, as both may be CD4+, CD7-, and CD25+, though CD25 positivity usually is more variable in CTCL and confined to a minor subset of cells. The key distinguishing feature is the presence of HTLV-I in the malignant cells of ATL. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

T-prolymphocytic leukemia — Like ATL, T-prolymphocytic leukemia (T-PLL) is an aggressive malignancy. It is characterized by circulating malignant T lymphoid cells, marked lymphocytosis, cytopenias, and splenomegaly. Immunophenotype can help distinguish this disorder from ATL. As with ATL, T-PLL is CD4+. However, unlike ATL, T-PLL is CD7+ and CD25-. T-PLL is not associated with HTLV-I and >80 percent of tumors have genetic abnormalities, usually an inversion of chromosome 14 that fuses the TCL1 gene to the T cell receptor alpha/delta locus and leads to the overexpression of TCL1 protein. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

Anaplastic large cell lymphoma — Anaplastic large cell lymphoma (ALCL) is another T cell lymphoid neoplasm that primarily involves the lymph nodes and skin but can demonstrate circulating malignant cells. Cell morphology is varied and the tumor cells may be CD4+ and CD7-, like ATL. Immunohistochemistry staining can be of help since ALCL has strong, uniform expression of CD30 with a membrane and Golgi distribution and is usually cytotoxic granule-associated protein positive.

The diagnosis of ALCL can be confirmed in many cases by demonstrating an ALK1 gene rearrangement or expression of the ALK-1 protein, neither of which is found in ATL. The cutaneous variant of ALCL is much less likely than the systemic variant to demonstrate ALK-1 positivity and may be difficult to distinguish from ATL with cutaneous involvement; however, ALCL is not HTLV-1 associated, which is an important point of distinction. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Angioimmunoblastic T cell lymphoma — Angioimmunoblastic T cell lymphoma (AITL) is one of the most common peripheral T cell lymphomas and usually presents with generalized systemic symptoms, lymphadenopathy, hepatomegaly, bone marrow involvement, and a pruritic skin rash. Most patients demonstrate a polyclonal hypergammaglobulinemia. The morphology of the malignant cells is varied but one common feature is the prominent arborizing high endothelial venules not typically found in ATL. Immunophenotyping typically demonstrates CD4 positivity and decreased intensity of CD7; however, the cell of origin of AITL is a follicular helper T cell, and the tumor cell of AITL bears certain immunophenotypic features of follicular helper T cells, such as expression of PD-1, CXCL13, CD10, and BCL6, that are absent for ATL. Finally, unlike ATL, AITL is not HTLV-I associated. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

TREATMENT — The treatment of ATL is discussed separately. (See "Treatment and prognosis of adult T cell leukemia-lymphoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

SUMMARY

●Adult T cell leukemia-lymphoma (ATL) is an uncommon lymphoid neoplasm caused by human T-lymphotropic virus, type I (HTLV-I) infection. Incidence varies by population according to the prevalence of HTLV-I infection. (See 'Epidemiology' above.)

●The long-term risk of developing ATL following infection with HTLV-I in endemic areas has been estimated to be 4 to 5 percent, usually after a latency period of several decades. The exact mechanism by which HTLV-I contributes to tumor development is unknown. However, the viral tax oncoprotein (encoded by the viral tax gene) is associated with increased cellular proliferation and survival, and impaired DNA damage repair mechanisms. (See 'Pathogenesis' above.)

●The clinical features of ATL include evidence of generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, hypercalcemia, lytic bone lesions, and skin lesions. The frequency of these differs among patient groups and has been the basis on which clinical variants have been defined. There are four basic clinical variants of ATL: acute (60 percent of cases), lymphomatous (20 percent of cases), chronic (10 percent of cases) and smoldering (10 percent of cases); in addition, primary cutaneous variant is a provisional subtype. ATL can progress from a chronic or smoldering variant to an aggressive disease resembling the acute variant. (See 'Clinical features' above.)

●The most characteristic morphologic changes seen in the peripheral blood of ATL patients are cells with bizarre hyperlobulated nuclei ("clover leaf" or "flower cells") (picture 1). Bone marrow infiltrates are usually patchy. Involved lymph nodes typically display diffuse architectural effacement. Skin infiltrates can be similar to those seen in cutaneous T cell lymphoma (mycosis fungoides). (See 'Morphology' above.)

●The cell of origin in ATL is an HTLV-I infected (CD4+) T cell that may reside in a long-lived pool of memory T cells with stem-like cells properties. In the majority of cases, the tumor cells also express other T cell associated antigens (CD2 and CD5), lack CD7, and express the IL-2 receptor, CD25. (See 'Immunophenotype' above.)

●There is no distinct molecular or karyotypic abnormality in ATL. The T cell receptor genes are clonally rearranged, and all cases demonstrate clonally integrated HTLV-I. The more clinically aggressive ATL variants have the most complex chromosomal abnormalities. (See 'Genetics' above.)

●The diagnosis of ATL is based on a combination of specific clinical features, the morphology and immunophenotype of the malignant cells, and the presence of HTLV-I infection. The differential diagnosis of ATL includes other mature T cell lymphoid malignancies. (See 'Diagnosis' above and 'Differential diagnosis' above.)