• Cell of origin is peripheral CD4+ T regulatory αβ T cell (CD4+ CD25+ FoxP3+ T regulatory cells are the closest normal counterpart)
• ATLL patients suffer from profound immunodeficiency; the concept that the cell of origin of ATLL is a T regulatory T cell provides a biologic basis for disease associated immunodeficiency

Contributed by Jennifer Chapman, M.D.

• 4 clinically defined variants in Shimoyama classification: acute, lymphomatous, chronic and smoldering (Br J Haematol 1991;79:428)
• Acute variant: ~ 55 to 60% of cases, survival usually < 1 year
  • Leukocytosis (often greater than 100 x 10⁹/L)
  • Peripheral blood involvement with numerous flower cells
  • Skin rash and lymphadenopathy
  • Hepatosplenomegaly
  • Hypercalcemia
  • Elevated serum LDH
  • Rapidly progressive course and frequent opportunistic infections
• Lymphomatous variant: ~ 20% of cases, survival usually < 1 year
  • Lymphadenopathy
  • Skin lesions
  • No / minimal peripheral blood involvement
  • Hypercalcemia is less frequent (compared with acute variant)
• Chronic variant: ~ 15 to 20% of cases, survival > 2 years but < 5 years due to progression to acute or lymphomatous ATLL
  • Lymphocytosis
  • Exfoliative skin lesions
  • Lymphocyte count is much lower than in the acute variant
  • Few atypical lymphocytes in peripheral smear review
  • Mild hepatosplenomegaly
  • Mild lymphadenopathy
  • No hypercalcemia
• Smoldering variant: ~ 5% of cases, survival > 2 years but < 10 years due to progression to acute ATLL or infectious complications
  • Skin or lung lesions
  • More than 5% atypical lymphocytes in absence of leukocytosis
  • No hepatosplenomegaly, hypercalcemia or lymphadenopathy
• Primary cutaneous tumoral type
  • No leukemic phase, lymphadenopathy, hepatosplenomegaly or hypercalcemia
  • Proposed as a fifth clinical type in the Shimoyama classification (Int J Dermatol 2010;49:1099)
• Nonneoplastic HTLV-1 associated diseases
  • Tropical spastic paraparesis / HTLV-1 associated myelopathy (TSP / HAM)
  • HTLV-1-associated infective dermatitis
  • Uveitis
  • Thyroiditis
  • Pneumonitis
  • Myositis

LDH = lactate dehydrogenase; *may develop later in the course of disease

Comparison of clinical forms of adult T cell leukemia / lymphoma
Clinical manifestation	Acute	Lymphomatous	Smoldering	Chronic
Lymphocytosis	Increased	No	No	Mildly increased
Blood abnormal lymphocyte	Increased	No*	> 5%	Mildly increased
Increased LDH	Yes	No	No	Minimal
Hypercalcemia	Yes	Variable	No	No
Skin rash	Variable: > 50%	Variable: > 50%	Erythematous rash	Rash, papules
Lymphadenopathy	Usually present	Yes	No	Mild
Hepatosplenomegaly	Usually present	Often present	No	Mild
Bone marrow infiltration	May be present	No	No	No
Median survival	< 1 year	< 1 year	> 2 years	> 2 years

• Clinical variant, age, performance status, serum calcium and LDH levels are major prognostic factors
• Death often stems from opportunistic infections
• Acute and lymphomatous variants:
  • Aggressive clinical course
  • Recurrent infection: parasitic (Strongyloides stercoralis) and viral infections (Parasite Immunol 2004;26:487)
  • p16 gene deletion and p53 mutation: more aggressive clinical course
• Chronic and smoldering variants:
  • More protracted clinical course
  • Progression to an acute phase with an aggressive course in ~25%
  • p16 gene deletion and chromosomal deletion detected via comparative genomic hybridization (CGH) in the chronic phase is a negative prognostic factor (J Clin Oncol 1997;15:1778)

• Chronic or smoldering ATLL: observation may be appropriate for patients who are asymptomatic
• ATLL is resistant to most chemotherapy
• No standard chemotherapy regimen
• Intensive high dose combination chemotherapy and bone marrow transplantation have been used in limited numbers of patients (Blood 2010;116:1369)
• Monoclonal antibody based therapies have been attempted directed against:
  • IL-2R (anti-Tac)
  • CCR4 (mogamulizumab)
  • CD52 (alemtuzumab)
• Recent clinical trials use arsenic trioxide, interferon α and zidovudine (Adv Ther 2018;35:135)

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• Bone marrow:
  • Degree of bone marrow infiltration is less than expected, given the marked lymphocytosis that is often present
  • Pattern of marrow involvement can be diffuse, interstitial or sinusoidal
  • Often evidence of bone resorption and osteoclastic activity
  • Bone trabeculae: may show remodeling
  • Lytic bone lesions can be present even in the absence of tumoral bone infiltration
• Lymph nodes:
  • Involves paracortical T cell zones
  • Typically show diffuse architectural effacement
  • May be subdivided according to cell type and pattern into:
    • Pleomorphic small cell
    • Pleomorphic medium and large cell type / pattern (most common)
    • Anaplastic large cell-like [resembling anaplastic large cell lymphoma (ALCL)]
    • Angioimmunoblastic T cell lymphoma-like (AITL)
    • Hodgkin lymphoma-like: seen in early phase of some adult T cell lymphoma
    • Leukemic pattern of infiltration with preservation or dilation of lymph node sinuses that contain malignant cells
  • Size or shape of the neoplastic cells or identification / classification of the above patterns does not impact the clinical course
• Skin lesions:
  • Epidermal infiltration with Pautrier-like micro-abscesses is common (Mod Pathol 2018;31:1046)
  • Hyperparakeratosis is variably present in the overlying epidermis
  • Dermal infiltration: mainly perivascular but larger tumor nodules with extension to subcutaneous fat may be observed
  • Erythematous lesions: composed of smaller cells in perivascular pattern in dermis
  • Papules and nodules: composed of larger cells that replace dermis
• Other sites commonly involved by ATLL include: liver, spleen, lungs and central nervous system
• Grading: there is no formal grading system for ATLL

Note: ATLL should be strongly considered in any T cell lymphoma developing in a patient from an endemic area regardless of histopathologic features and anti-HTLV-1 serology testing should be performed

Contributed by Jennifer Chapman, M.D.

Contributed by Jennifer Chapman, M.D.


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Contributed by Jennifer Chapman, M.D.


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• Viral particles, 80 to 120 nm, are present in both cytoplasm and extracellular space

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• Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS)
  • Patient from Western hemisphere
  • Background of reactive cells, including eosinophils, plasma cells and histiocytes
  • Negative serologic studies or lack of molecular evidence of HTLV-1
• Angioimmunoblastic T cell lymphoma (AITL)
  • CD10+, PD-1+, Bcl6+ or CXCL13+ lymphoma cells
  • Irregular and expanded proliferation of CD21+ follicular dendritic cells
  • Prominent hyalinized vascular proliferation
  • Hypergammaglobulinemia and eosinophilia
  • Significant B cell infiltration, including large B cells and monoclonal IGH gene rearrangements
• Anaplastic large cell lymphoma (ALCL)
  • Sinusoidal distribution in partially involved lymph nodes
  • Lymphoma cells are strongly CD30+ (ATLL with strong CD30 expression in 100% of lymphoma cells are reported)
  • Expression of cytotoxic granule associated proteins (can be seen in ATLL)
  • Translocations involving ALK gene and / or ALK1 protein expression
  • ALK- ALCL cases are difficult to differentiate from ATLL without HTLV-1 testing
• Classic Hodgkin lymphoma (HL)
  • Background T cells are immunophenotypically normal
  • Lacks clonal T cell gene rearrangement
  • Lacks malignant cells in peripheral blood, rare reports of skin lesions and hypercalcemia
• Cutaneous T cell lymphoma / mycosis fungoides (CTCL MF / SS)
  • Sézary cells are cerebriform, small, hyperchromatic
  • CD25 is variably + in MF / SS; strong + in ATLL
  • MF / SS is usually not CD25+, FOXP3+ or CD30+
  • Patients not infected with HTLV-1 virus
• T cell prolymphocytic leukemia (T-PLL)
  • Involves blood at presentation with ↑ WBC
  • Some nuclear irregularity but no flower cell morphology as in ATLL
  • Lack of anti-HTLV-1 positive serology
• T lymphoblastic leukemia / lymphoma (T-LBL)
  • Large mediastinal mass in adolescent or young adult
  • TdT+, CD1a+
• T cell large granular lymphocytic leukemia (LGL)
  • Peripheral blood lymphocytes have increased pale cytoplasm and prominent azurophilic granules
  • Mild nuclear indenting but no polylobated nuclei as in ATLL
  • CD8+, CD16+, CD57+

• Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th Edition, 2008, His: Hematopathology - Foundations in Diagnostic Pathology series, 3rd Edition, 2017, Orazi: Knowles Neoplastic Hematopathology, 3rd Edition, 2013, Jaffe: Hematopathology 2nd, Edition, 2016, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Which of the following is the most common site of extranodal involvement in adult T cell leukemia / lymphoma (ATLL)?

1. Central nervous system
2. Heart
3. Liver
4. Skin

D. Skin

Comment here

A 67 year old Haitian man with hepatitis B presents with fatigue and weakness. No other symptoms are present. Laboratory work up shows leukocytosis (55 x 10⁹/L) and thrombocytopenia (100 x 10⁹/L). Physical examination and imaging studies show massive splenomegaly with no lymphadenopathy. There was no hypercalcemia or increased in serum LDH. Peripheral smear review showed abnormal lymphocytosis with circulating lymphoma cells having mature nuclear features and highly lobulated nuclei. Flow cytometry performed in bone marrow aspirate is provided below. Serology for anti HTLV-1 antibody is positive. Which of the following is the most accurate statement?

1. Dual positivity for CD4 and CD8 is uncommon in adult T cell leukemia / lymphoma
2. Expression of CD25 is specific for ATLL among T cell lymphomas / leukemias
3. Patient has acute myeloid leukemia with maturation (NK / myeloid type)
4. Patient has T cell large granular lymphocytic leukemia (LGL)

A. Dual positivity for CD4 and CD8 is uncommon in adult T cell leukemia / lymphoma

Comment here