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Hematological System ORGAN SYSTEMS

Adult T‐cell leukemia/lymphoma (ATLL)

HTLV-I virus infecting a human T-lymphocyte, causing a risk of developing leukemia
Scanning electron micrograph of HTLV-I virus (green) infecting a human T-lymphocyte (yellow). Infection with this virus can stimulate the T-cells to proliferate at an increased rate, causing a risk of developing leukemia. | Dr. Dennis Kunkel/Phototake

Aggressive mature T‐lymphoid malignancy of post‐thymic pleomorphic activated T lymphocytes caused by human T-cell leukemia virus type I (HTLV-1) infection .

Non-Hodgkin lymphoma (NHL):

Non-Hodgkin's lymphoma subtypes and their incidence
Bowzyk Al-Naeeb, A., Ajithkumar, T., Behan, S., & Hodson, D. J. (2018). Non-Hodgkin lymphoma. BMJ, 362, k3204. https://doi.org/10.1136/bmj.k3204

History:

Adult T-cell leukemia (ATL) was first reported as a distinct clinical entity in Japan in 1977. The clustering of patients in the southwestern part of Japan propelled Japanese investigators to the interest that the disease could be virally induced. Subsequently, human T-cell leukemia virus type I (HTLV-1) was discovered as the causative virus for ATL in 1982. The discoveries of ATL and HTLV-1 ushered in the development of virology, oncology, molecular biology, epidemiology, and other fields of medicine.

Microbiology

Human T-cell leukaemia virus type I (HTLV-1):

Adult T cell leukemia is primarily caused by HTLV-1 infection that usually remains asymptomatic. Transactivator protein (tax) and HTLV-1 basic leucine zipper factor (HBZ), the two viral oncoproteins, play an essential role in the development of disease and progression. Tax protein expression takes part in the onset of neoplastic transformation. HBZ protein is expressed on all infected malignant cell lines, which is responsible for the proliferation of leukemic cells.[4]
Comparison of molecular abnormalities between HTLV-1–infected T cells and transformed ATL cells
Comparison of molecular abnormalities between HTLV-1–infected T cells and transformed ATL cells: Many aspects of the ATL cell phenotype share common characteristics with that of untransformed HTLV-1–infected T cells expressing viral proteins, including Tax. Tax was shown to induce the majority of molecular changes observed in HTLV-1–infected cells, most of which are preserved in ATL cells that do not express Tax. Thus, this phenomenon is sometimes referred to as the signature of Tax. CARD11, caspase recruitment domain-containing protein 11; GPR183, G-protein coupled receptor 183; NRXN3, neurexin-3; PLCG1, phospholipase C, γ 1; PRKCB, protein kinase C β | Watanabe, T. (2017). Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells. Blood, 129(9), 1071 LP-1081. Retrieved from http://www.bloodjournal.org/content/129/9/1071.abstract

Epidemiolgy:

  • Endemicity: North and south parts of Japan, the Caribbean region, Africa, some parts in the Middle East, South, and Central America
  • Transmission: Breastfeeding, sexual interaction, and blood transfusion.

Presentation

Initial presentation may vary, including generalized lymph node swelling, hepatosplenomegaly, skin involvement, and opportunistic infections.

Clinical classification:

ATL is classified into four clinical subtypes according to the Shimoyama criteria
  • Acute ATL (>50% cases): Presents with leukemic pictures, systemic symptoms, lymphadenopathy, organ infiltration, hypercalcemia, and high serum lactate dehydrogenase (LDH) level
  • Chronic ATL: Characterized by presence of skin, lung and liver involvement, lymphocytosis (≥4 × 103 cells/μL) with normal LDH, and calcium
    • Further two subgroups: favorable (better prognosis) and unfavorable (poorer prognosis with at least one poor prognostic factor such as elevated LDH, elevated BUN, and decreased albumin)
  • Lymphomatous ATL: Characterized by extensive lymphadenopathy, organomegaly, markedly increased LDH, hypercalcemia, and < 1% presence of circulating leukemic cells in the peripheral blood.
  • Smoldering ATL: Presents with lung or skin involvement, normal lymphocyte count, normal or mildly increased LDH
Schematic description of clonal progression and phenotypic changes
Schematic description of clonal progression and phenotypic changes: HTLV-1–infected T cells and ATL cells in vivo are now available for molecular analyses. Accumulating data indicate that epigenetic abnormalities occur early during leukemogenesis, as untransformed HTLV-1–infected cells show evidence of epigenetic abnormalities that are observed in ATL cells as well. The extent of clonality during HTLV-infection and progression to ATL have been characterized in detail by recent studies that provide information on clonal progression based on integration sites. | Watanabe, T. (2017). Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells. Blood, 129(9), 1071 LP-1081. Retrieved from http://www.bloodjournal.org/content/129/9/1071.abstract

Cutaneous involvement:

All forms of ATL may demonstrate variable skin findings.

Tumor lysis syndrome, as well as central nervous system involvement, may be seen in aggressive ATL. Due to severe immunosuppression, all ATL patients are at increased risk for infections, including fungal, viral, and parasitic infections, specifically strongyloidiasis.

Examples of cutaneous lesions observed in ATLL
Examples of cutaneous lesions observed in ATLL: A. Chronic form with papular pattern. B. Acute form showing exfoliative erythroderma. C. Smoldering form with a pattern of papules and erythematous scaly plaques. D. Primary cutaneous tumoral form. | Oliveira, P. D., Farre, L., & Bittencourt, A. L. (2016). Adult T-cell leukemia/lymphoma. Revista da Associacao Medica Brasileira (1992), 62(7), 691–700. https://doi.org/10.1590/1806-9282.62.07.691

Diagnosis

Diagnosis of adult T cell leukemia requires a comprehensive history review in conjunction with laboratory and pathologic survey.

Peripheral blood smear:

In the acute and chronic leukemic phase, the WBC count may increase with circulating atypical cells.
  • Flower cell or cloverleaf (PATHOGNOMIC): Condensed chromatin with a convoluted or polylobated nucleus
Circulating lymphocytes in a patient with adult T‐cell leukaemia/lymphoma, showing a convoluted polylobated nucleus
Circulating lymphocytes in a patient with adult T‐cell leukaemia/lymphoma, showing a convoluted polylobated nucleus. May Grumwald Giemsa stain. | Matutes E. (2007). Adult T-cell leukaemia/lymphoma. Journal of clinical pathology, 60(12), 1373–1377. https://doi.org/10.1136/jcp.2007.052456

Molecular diagnosis:

The sensitivity for the diagnosis of HTLV-1 is higher with ELISA than with Western Blot and negative test rules out ATL
  • ELISA
  • Western Blot and/or PCR (if Western Blot is indeterminate)
A. Flower cell on blood smear. B. Southern blot demonstrating monoclonal proviral integration
A. Flower cell on blood smear. B. Southern blot demonstrating monoclonal proviral integration. | M: marker; P: patient. | Oliveira, P. D., Farre, L., & Bittencourt, A. L. (2016). Adult T-cell leukemia/lymphoma. Revista da Associacao Medica Brasileira (1992), 62(7), 691–700. https://doi.org/10.1590/1806-9282.62.07.691

Tissue biopsy:

Excisional lymph node biopsy, skin biopsy, and GI tract biopsy in conjunction with flow cytometry and immunohistochemistry (IHC) are helpful for the diagnosis. Bone marrow aspiration and biopsy may also be needed for diagnosis and staging.
Skin biopsy of ATLL
A. Skin biopsy of a patient with the chronic form and with a pattern of mycosis fungoides. Infiltration of small and medium lymphocytes in the superficial dermis, with pagetoid infiltration of the epidermis (HE, 100x). B. Skin biopsy of a patient with the primary tumor of skin form and with a pattern of peripheral T-cell lymphoma not otherwise specified. Note the accentuated cellular pleomorphism (HE, 500x). C. Biopsy of the same patient in figure B, showing a high proliferative index (Ki-67, 400x). D. Lymph node of chronic patient with a Hodgkin’s lymphoma pattern. Reed-Sternberg and Hodgkin type cells seen amid a background of medium sized lymphocytes, with a T-cell phenotype (HE, 400x). A Reed-Sternberg cell highlighted in the lower right corner (HE, 560x). | Oliveira, P. D., Farre, L., & Bittencourt, A. L. (2016). Adult T-cell leukemia/lymphoma. Revista da Associacao Medica Brasileira (1992), 62(7), 691–700. https://doi.org/10.1590/1806-9282.62.07.691
  • Flow cytometry & immunohistochemistry (IHC):
    • Express: CD2, CD4, CD5, CD45RO, CD29, and T-cell receptor αβ
    • Do not express: CD7, CD8, or CD26
    • Reduced expression: CD3
Flow cytometry dot plot of peripheral lymphocytes of a patient with adult T‐cell leukaemia/lymphoma
Flow cytometry dot plot of peripheral lymphocytes of a patient with adult T‐cell leukaemia/lymphoma, showing a characteristic immunophenotypic profile: CD3+, CD4+, CD7−, CD8−, CD25+ | Matutes, E. (2007). Adult T-cell leukaemia/lymphoma. Journal of Clinical Pathology, 60(12), 1373–1377. https://doi.org/10.1136/jcp.2007.052456

Differential diagnosis:

The differential diagnosis of ATLL includes other mature T‐cell neoplasms
  • T‐cell prolymphocytic leukaemia (T‐PLL)
  • Sézary syndrome (SS)
  • Peripheral T‐cell lymphomas
  • Hodgkin disease

Management

Treatment is tailored according to clinical subtype and patients characteristics. Chemotherapy or antiviral regimen is generally the first-line treatment for aggressive type (acute, lymphoma, and chronic with unfavorable features). Antiviral regimen or watchful waiting is a reasonable first-line for smoldering and favorable chronic subtypes. For skin lesions, ultraviolet B (NB-UVB) and psoralen and ultraviolet A (PUVA) can be used.

Antiviral therapy:

Patients with leukemic forms of ATL showed improved results with first-line antiviral therapy (zidovudine and interferon), whereas patients with lymphoma type showed a better outcome with chemotherapy.
  • Zidovudine (AZT) + interferon (IFN)

Chemotherapy

  • Standard chemotherapeutic regimen:
    • VCAP-AMP-VECP (LSG-15) regimen: Vincristine, cyclophosphamide, doxorubicin, prednisone-doxorubicin, ranimustine, and prednisone-vindesine, etoposide, carboplatin, prednisone
  • Alternative regimens:
    • Modified EPOCH regimen: Etoposide, prednisolone, vincristine, carboplatin, and doxorubicin; carboplatin is substituted for cyclophosphamide)
    • Hyper-CVAD regimen: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone
    • CHOP regimen: Cyclophosphamide, doxorubicin, vincristine, and prednisone
    • CHOEP regimen: Cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone

Allogeneic Stem Cell Transplantation

Monoclonal Antibody Therapy Brentuximab Vedotin

  • Brentuximab vedotin (BV): CD30-directed monoclonal antibody
  • Mogamulizumab: Humanized anti-CCR4 monoclonal antibody (approved for relapsed/resistant ATL in Japan)
  • Alemtuzumab: Humanized monoclonal antibody against CD52
  • Daclizumab: Humanized monoclonal antibody that binds to CD25 (interleukin-2 receptor alpha chain) that is over-expressed on ATL cells

Prognosis:

Patients who have rapidly progressive disease carry a poor prognosis due to the chemo-resistance of malignant cells and severe immunosuppression.
  • Aggressive ATL (acute, lymphoma, and chronic (unfavorable) type): Have a poor prognosis with an overall survival rate of less than a year
  • Favorable chronic and smoldering subtypes: Carry a relatively good prognosis, and watchful waiting is generally preferred until disease progression occurs

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