Adult T-cell leukemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2], Aida Javanbakht, M.D.; Grammar Reviewer: Natalie Harpenau, B.S.[3]

The exact mechanism of pathogenesis of the adult T‐cell leukemia is unknown. Adult T‐cell leukemia arises from post‐thymic lymphocytes, which are normally involved in the process of cell-mediated immune response. Development of adult T-cell leukemia is the result of multiple genetic mutations induced by an infection with human T‐cell lymphotropic virus (HTLV). On gross pathology, skin nodules, maculopapular eruption, and erythema are characteristic skin findings of adult T-cell leukemia. On microscopic histopathological analysis, characteristic findings of adult T-cell leukemia include pleomorphic, medium sized lymphocytes with a polylobulated nucleus and agranular cytoplasm.

The exact mechanism of pathogenesis of the adult T‐cell leukemia is unknown.

• Adult T‐cell leukemia arises from post‐thymic lymphocytes, which are normally involved in the process of cell-mediated immune response.^{[1][2][3][4][5]}
• Adult T‐cell leukemia is mainly caused by an infection with human T‐cell lymphotropic virus (HTLV).^[6]
• HTLV is usually transmitted via breast feeding early in life. Other minor routes of transmission for HTLV may include sexual contact, exposure to contaminated blood, or vertical maternal transmission.^[7]
• It appears to be a long latent period between HTLV-1 infection and the development of adult T‐cell leukemia.
• The oncogenesis of HTLV infection, which results in the development of adult T-cell leukemia, is due to:

• HTLV basic leucine zipper factor
• HTLV p40 tax viral protein
• Activation of JAK/STAT signaling pathway by HTLV
• Enhancement of CREB transcription factor by HTLV

• Adult T‐cell leukemia can manifests as either a leukemic form (75% of the cases) or a pure lymphomatous form (25% of the cases).
• Adult T‐cell leukemia is a widely disseminated disease, which may involve the peripheral blood cells, bone marrow, lymph nodes, liver, spleen, skin, and CNS.
• Hematopathological features of adult T-cell leukemia are variable, which may include:

• Anemia
• Thrombocytopenia
• Neutrophilia
• Eosinophilia

• Patchy bone marrow infiltration among adult T-cell leukemia patients may result in:

• Tumor-induced osteolysis due to increased osteoclastic activity
• Multiple lytic bone lesions
• Hypercalcemia

• Hypercalcemia among adult T-cell leukemia patients has been associated with elevated serum concentrations of:

• IL-1
• TGFβ
• PTHrP
• MIP-1α
• RANKL

• Infiltration of malignant leukemic cells results in the expansion of the lymph nodes paracortical region, which may lead to the development of peripheral lymphadenopathy among adult T-cell leukemia patients.
• Infiltration of the liver and spleen may lead to the development of organomegaly among adult T-cell leukemia patients.
• Cutaneous manifestations of adult T-cell leukemia is due to the infiltration of leukemic cells along the dermis layer of the skin.
• Cutaneous Pautrier’s microabscesses formation (due to epidermotropism) may also be present among adult T-cell leukemia patients. These cutaneous lesions are indistinguishable from the ones found in Sézary syndrome and mycosis fungoides.
• Immune deficiency occurs in adult T-cell leukemia due to a defective cell-mediated immunity.

• Development of adult T-cell leukemia is the result of multiple genetic mutations.^{[1][2][3][4][5]}

• Genes involved in the pathogenesis of adult T-cell leukemia include:
  • 14q11 gene mutation
  • TCR‐alpha chain gene mutation
  • TCR‐delta chain gene mutation

• On gross pathology, skin nodules, maculopapular eruption, and erythema are characteristic findings of adult T-cell leukemia.^[5][8]

• On microscopic histopathological analysis, characteristic findings of adult T-cell leukemia include:

• Pleomorphic, medium-sized lymphocytes
• Convoluted or polylobulated nucleus with condensed chromatin (cloverleaf nuclei)
• Nucleoli are not visible
• Agranular cytoplasm
• “Flower cells”
• Reed-Sternberg-like cells may also be present

• On immunohistochemical analysis, characteristic findings of adult T-cell leukemia include ^[9]:

• CD2 positive
• CD3 positive
• CD4 positive
• CD5 positive
• CD7 positive
• CD8 negative
• CD20 positive
• CD25 positive
• CD79a positive
• CD3 and T‐cell receptor (TCR)‐β may be down‐regulated