Adult T-cell leukemia

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

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. Based on both the clinical presentation and lab values, adult T-cell leukemia may be classified into either an acute variant, chronic variant, smoldering variant, or an adult T-cell lymphoma variant. The majority of adult T-cell leukemia cases are reported in Japan, the Caribbean, South America, and Africa. The natural history of adult T-cell leukemia varies between the different sub-types of the disease. Common complications of adult T-cell leukemia include cardiac arrhythmias, opportunistic infections, and bone fractures. The prognosis varies between the sub-types of adult T-cell leukemia. Acute and lymphomatous sub-types have a poor prognosis; whereas chronic and smoldering sub-types have a good prognosis. The optimal therapy for adult T-cell leukemia depends on the clinical variant of the disease. Chronic and smoldering adult T-cell leukemia patients are usually managed by either observation, skin directed therapies, or a combination of zidovudine and interferon therapy. Acute adult T-cell leukemia patients are usually managed by either chemotherapy, supportive care, allogeneic stem cell transplant, or a combination of zidovudine and interferon therapy. The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include CHOP, CHOEP, or Dose-adjusted EPOCH. Second line chemotherapeutic agents might be DHAP, ESHAP, GDP, GemOx, or ICE. Surgery is not the first-line treatment option for patients with adult T-cell leukemia. Splenectomy is usually reserved for certain cases of adult T-cell leukemia. No preventive vaccine against HTLV-1 is currently available.

Adult T-cell leukemia was first discovered in 1977 by Dr. K. Takatsuki, a Japanese physician. The association between HTLV infection and adult T-cell leukemia was made in 1981.

Based on both the clinical presentation and laboratory findings, adult T-cell leukemia may be classified into either an acute variant, chronic variant, smoldering variant, or an adult T-cell lymphoma variant.

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.

Adult T-cell leukemia is caused by an infection with HTLV. Common genetic mutations involved in the development of adult T-cell leukemia can be found here.

Adult T-cell leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukemia, prolymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.

The majority of adult T-cell leukemia cases are reported in Japan, the Caribbean, South America, and Africa. In southern Japan, the age-adjusted incidence rate of adult T-cell leukemia is approximately 6.6 per 100,000 individuals. The incidence of adult T-cell leukemia increases with age, and the median age at diagnosis is 57 years. Males are more commonly affected with adult T-cell leukemia than females. The male to female ratio is approximately 1.4 to 1. Adult T-cell leukemia usually affects individuals of the African American, Latin American, and Asian race. Caucasian individuals are less likely to develop adult T-cell leukemia.

Common risk factors in the development of adult T-cell leukemia among HTLV carriers are vertical transmission of HTLV infection during labor, male sex, and specific human leukocyte antigens such as HLA-A 26, HLA-B 4002, and HLA-B 4801.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for adult T-cell leukemia.

The natural history of adult T-cell leukemia varies between the different sub-types of the disease. Common complications of adult T-cell leukemia include cardiac arrhythmias, opportunistic infections , and bone fractures. The prognosis varies between the sub-types of adult T-cell leukemia. Acute and lymphomatous sub-types have a poor prognosis; whereas chronic and smouldering sub-types have a good prognosis.

There is no single diagnostic study of choice for the diagnosis of adult T-cell leukemia. However, adult T-cell leukemia can be diagnosed based on clinical manifestation and laboratory findings confirming characteristic histopathology and HTLV-1 infection.

Symptoms of adult T-cell leukemia include fatigue, fever, night sweats, constipation, and recurrent infections.

Patients with adult T-cell leukemia usually appear lethargic and fatigued. Physical examination of patients with adult T-cell leukemia is usually remarkable for maculopapular rash, skin ulceration, and splenomegaly.

Laboratory findings consistent with the diagnosis of adult T-cell leukemia include abnormal anemia, thrombocytopenia, and elevated lymphocyte count. Hypercalcemia is a key feature among patients with adult T-cell leukemia.

There are no ECG findings associated with adult T-cell leukemia. However, electrocardiogram might be helpful in detecting complications of adult T-cell leukemia such as cardiac arrhythmias due to hypercalcemia. To view the electrocardiogram findings in hypercalcemia, click here.

There are no x-ray findings associated with adult T-cell leukemia. However, an x-ray may be helpful in the diagnosis of complications of adult T-cell leukemia, which include bone fractures and lytic lesions.

There are no echocardiography findings associated with adult T-cell leukemia. Findings on an ultrasound suggestive of adult T-cell leukemia include hepatomegaly, splenomegaly and lymphadenopathy.

Thoracic CT scan may be helpful in the diagnosis of adult T-cell leukemia. Findings on CT scan suggestive of pulmonary infiltration by adult T-cell leukemia cells include thickening of the bronchovascular bundles, consolidation in the peripheral lung parenchyma, and ground-glass attenuations. Findings on abdominal CT scan suggestive of adult T-cell leukemia cells include hepatomegaly and splenomegaly.

There are no MRI findings associated with adult T-cell leukemia.

There are no other imaging findings associated with adult T-cell leukemia.

Other diagnostic studies for adult T-cell leukemia include skin biopsy, bone marrow biopsy, and fluorescent in-situ hybridization.

The optimal therapy for adult T-cell leukemia depends on the clinical variant of the disease. Chronic and smoldering adult T-cell leukemia patients are usually managed by either observation, skin directed therapies, or a combination of zidovudine and interferon therapy. Acute adult T-cell leukemia patients are usually managed by either chemotherapy, supportive care, allogeneic stem cell transplant, or a combination of zidovudine and interferon therapy. The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include CHOP, CHOEP, or Dose-adjusted EPOCH. Second line chemotherapeutic agents might be DHAP, ESHAP, GDP, GemOx, or ICE.

The mainstay of treatment for Adult T-cell leukemia is medical therapy. There are no recommended therapeutic interventions for the management of Adult T-cell leukemia.

Surgery is not the first-line treatment option for patients with adult T-cell leukemia. Splenectomy is usually reserved for certain cases of adult T-cell leukemia.

Primary prevention of adult-T cell leukemia is aimed at preventing the vertical and person-person transmission of HTLV virus. No preventive vaccine against HTLV-1 is currently available.

There are no established measures for the secondary prevention of Adult T-cell leukemia.

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

Adult T-cell leukemia was first discovered in 1977 by Dr. K. Takatsuki, a Japanese physician. The association between HTLV infection and adult T-cell leukemia was made in 1981.

• Adult T-cell leukemia was first discovered in 1977 by Dr. K. Takatsuki, a Japanese physician.^[1][2]
• The association between HTLV infection and adult T-cell leukemia was made in 1981.

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]

Based on both the clinical presentation and laboratory findings, adult T-cell leukemia may be classified into either an acute variant, chronic variant, smoldering variant, or an adult T-cell lymphoma variant.

• Based on both the clinical presentation and laboratory findings, adult T-cell leukemia may be classified into either an acute variant, chronic variant, smoldering variant, or an adult T-cell lymphoma variant.^[1][2]
• The table below lists the adult T-cell leukemia clinical classification details:

Clinical Variant	Description
Acute adult T-cell leukemia[3]	Leukemic clinical presentation Organomegaly present Markedly elevated lactate dehydrogenase (LDH) level Hypercalcaemia
Chronic adult T-cell leukemia	Lymphocyte count greater than 4×109/L Cutaneous, pulmonary, and hepatic involvement Lymphadenopathy Normal serum LDH level (or less that twice the normal upper limit) Normal serum calcium level
Primary cutaneous tumoral (PCT)	Cutaneous involvement; nodules on the skin Poor prognosis. Normal serum LDH level (or less that twice the normal upper limit) Normal serum calcium level
Smoldering adult T-cell leukemia[1]	Cutaneous and/or pulmonary infiltrates No other organ involvement Normal lymphocyte count (1–5% ATLL cells) Normal serum LDH level Normal serum calcium level
Adult T-cell lymphoma[4]	Organomegaly present Less than 1% leukemic cells in the circulation Elevated serum LDH level Hypercalcemia

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

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

Adult T-cell leukemia is caused by an infection with HTLV. Common genetic mutations involved in the development of adult T-cell leukemia can be found here.

Adult T-cell leukemia is caused by an infection with HTLV. Common genetic mutations involved in the development of adult T-cell leukemia can be found here.^[1][2][3]

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

Adult T-cell leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukaemia, prolymphocytic leukaemia, follicular lymphoma, and mantle cell lymphoma.

• Adult T-cell leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukaemia, prolymphocytic leukaemia, follicular lymphoma, and mantle cell lymphoma.^[1][2][3][4]
• Based on the expression of cell surface markers, the table below differentiates adult T-cell leukemia from other diseases that cause similar clinical presentations:

Differential Diagnosis	Surface Immunoglobulin	CD5	CD22/FMC7	CD23	CD79b	CD103
Chronic lymphocytic leukemia	Weakly positive	Positive	Negative	Positive	Negative	Positive/Negative
Prolymphocytic leukemia	Strongly positive	Negative	Positive	Negative	Positive	Negative
Hairy cell leukemia	Strongly positive	Negative	Positive	Negative	Positive/Negative	Positive
Mantle cell lymphoma	Positive	Positive	Strongly positive	Negative	Strongly positive	Negative
Follicular lymphoma	Strongly positive	Negative	Positive	Negative	Strongly positive	Negative

• Adult T-cell leukemia must also be differentiated from other causes of fever, hepatosplenomegaly, and lymph node swelling such as:

• Splenic marginal zone lymphoma
• Nodal marginal zone lymphoma
• Lymphoplasmacytic lymphoma
• Sézary syndrome

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

The majority of adult T-cell leukemia cases are reported in Japan, the Caribbean, South America, and Africa. In southern Japan, the age-adjusted incidence rate of adult T-cell leukemia is approximately 6.6 per 100,000 individuals. The incidence of adult T-cell leukemia increases with age, and the median age at diagnosis is 57 years. Males are more commonly affected with adult T-cell leukemia than females. The male to female ratio is approximately 1.4 to 1. Adult T-cell leukemia usually affects individuals of the African American, Latin American, and Asian race. Caucasian individuals are less likely to develop adult T-cell leukemia.

• Human T-Lymphotropic Virus type 1 (HTLV-1) infects at least 5–10 million people worldwide.^[1]
• HTLV-1 is endemic to Central Australia and infection prevalence in this region ranges from a low of 7200 per 100,000 to a high of 13,900 per 100,000 of socially disadvantaged indigenous adults.^[2][3][4]
• In Australia, HTLV-1 carriers were first reported among indigenous residents of remote desert communities in 1988.^[5]
• Breastfeeding is thought to play an important role in transmission of HTLV-1 in indigenous Australian population.^[6]
• In the US, adult T-cell leukemia is considered a rare disease that mainly tends to develop among African American intravenous drug abusers.^[7]
• The majority of adult T-cell leukemia cases are reported in Japan, the Caribbean, South America, and Africa.

•  Among HTLV-1 carriers in high prevalence regions such as Central Australia, Japan and Carribean, adult T-cell leukemia/lymphoma (ATLL) will ultimately develop in 1-5% of infected individuals.^[8]
• In southern Japan, the age-adjusted incidence rate of adult T-cell leukemia is approximately 6.6 per 100,000 individuals.^[9][10][11]

• The annual incidence of adult T-cell leukemia development among HTLV-1 carriers is approximately 60 per 100,000 individuals.

• The incidence of adult T-cell leukemia increases with age,and the median age at diagnosis is 57 years.^[7]
• The age of onset for adult T-cell leukemia differs across geographical regions, such as:

• The median age at diagnosis in Japan is 60 years.
• The median age at diagnosis in Central America is 40 years.

• Males are more commonly affected with adult T-cell leukemia than females. The male to female ratio is approximately 1.4 to 1.^[9][10][11]
• Females are more commonly affected with HTLV infection than males. However, the risk of adult T-cell leukemia development among HTLV male carriers is five fold higher than the risk of adult T-cell leukemia development among HTLV female carriers.

• Adult T-cell leukemia usually affects individuals of the African American, Latin American, and Asian race.
• Caucasian individuals are less likely to develop adult T-cell leukemia.^[9][10][11]

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

Common risk factors in the development of adult T-cell leukemia among HTLV carriers are vertical transmission of HTLV infection during labor, male sex, and specific human leukocyte antigens such as HLA-A 26, HLA-B 4002, and HLA-B 4801.

• Common risk factors in the development of adult T-cell leukemia among HTLV carriers include:^[1][2][3]

• Vertical transmission of HTLV infection during labor
• Male sex
• Specific human leukocyte antigens such as:

• HLA-A 26
• HLA-B 4002
• HLA-B 4801

• Patients with a Strongyloides stercoralis co-infection
• Smoking
• An elevated soluble interleukin-2 receptor levels (> 500 U/ml)
• An elevated anti-HTLV-1 antibody titer
• An elevated HTLV proviral load level (> 4 copies per 100 peripheral blood mononuclear cells)
• An elevated WBC count (> 9,000/μL)
• An elevated abnormal lymphocyte count
• A decreased level of anti-Tax reactivity

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for adult T-cell leukemia.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for adult T-cell leukemia.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

The natural history of adult T-cell leukemia varies between the different subtypes of the disease. Common complications of adult T-cell leukemia include cardiac arrhythmias, opportunistic infections , and bone fractures. The prognosis varies between the subtypes of adult T-cell leukemia; acute and lymphomatous subtypes have a poor prognosis, where as chronic and smouldering subtypes have a good prognosis.

• The natural history of adult T-cell leukemia varies between the different subtypes of the disease.^[1]
• Usually patients with acute adult T-cell leukemia have an aggressive clinical course with a median survival period of less than 12 months. If left untreated, most of the patients with acute adult T-cell leukemia will develop constitutional symptoms, lymphadenopathy, and organomegaly within a few weeks of diagnosis.
• Usually patients with chronic adult T-cell leukemia will have an stable clinical course. If left untreated, most of the patients with chronic adult T-cell leukemia will develop lymphocytosis for months, or even years, before presenting with the typical cutaneous manifestations.
• Most patients with smoldering adult T cell leukemia are initially asymptomatic. If left untreated, most of the patients with smoldering adult T cell leukemia will develop steroid-responsive skin rash and multiple lung infiltrates.

• Common complications of adult T-cell leukemia include:^[1][2]

• Cardiac arrhythmias (due to hypercalcaemia)
• Opportunistic infections (Strongyloides stercoralis infection is a frequent cause of death among adult T-cell leukemia patients)
• Bone fractures (due to lytic bone lesions)
• Anemia
• Recurrent bleeding

• The prognosis varies between the subtypes of adult T-cell leukemia; acute and lymphomatous subtypes have a poor prognosis, where as chronic and smoldering subtypes have a good prognosis.^[3]

• The 4-year overall survival rate of patients with acute adult T-cell leukemia is approximately 11%.
• The 4-year overall survival rate of patients with adult T-cell lumphoma is approximately 16%.
• The 4-year overall survival rate of patients with chronic adult T-cell leukemia is approximately 36%.
• The 4-year overall survival rate of patients with smouldering adult T-cell leukemia is approximately 52%.

• The table below lists prognostic factors for adult T-cell leukemia patients:^{[1][3][4] [5]}

Prognostic Factor	Description
Clinical subtype	Acute and lymphomatous subtypes have a poor prognosis, where as chronic and smouldering subtypes have a good prognosis.
Gender	Males are associated with a worse prognosis when compared to females.
Performance status	Patient’s poor performance status is associated with a worse prognosis.
Proliferative index higher than 18%	is associated with a worse prognosis.
Calcium level	Hypercalcemia is associated with a worse prognosis.
Lactate dehydrogenase (LDH) level	Elevated level of LDH is associated with a worse prognosis.
β2-microglobulin level	An elevated β2-microglobulin level is associated with a worse prognosis.
Lymphocyte surface markers	Over expression of CD25 is associated with a worse prognosis.
Neuron‐specific enolase	An elevated neuron‐specific enolase level is associated with a worse prognosis.

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