Lymphoma and plasma cell neoplasms
Aggressive NK / T cell disorders
Adult T cell leukemia / lymphoma

Senior Author: Jennifer Chapman, M.D.
Editor-in-Chief: Debra Zynger, M.D.
Mahsa Khanlari, M.D.
Jennifer Chapman, M.D.

Topic Completed: 28 January 2019

Revised: 3 April 2019

Copyright: 2001-2019, PathologyOutlines.com, Inc.

PubMed Search: (Adult T cell leukemia / lymphoma [title]) (HTLV-1 positive)

Mahsa Khanlari, M.D.
Jennifer Chapman, M.D.
Page views in 2018: 3,093
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Cite this page: Khanlari M, Chapman J. Adult T cell leukemia / lymphoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomanonBatlv.html. Accessed July 20th, 2019.
Definition / general
  • Aggressive T cell malignancy of mature CD4+ T cells causally associated with human T lymphotropic virus 1 (HTLV-1; also called human T cell leukemia virus) (Blood 2017;129:1071)
Essential features
  • Lymphoma cells show monoclonal integration of HTLV-1 (Blood 2017;129:1071)
  • Occurs in regions endemic for HTLV-1 (~ 2.5% in HTLV-1 carriers) (Int J Hematol 2002;76:240)
  • Affected individuals are usually exposed to HTLV-1 very early in life (Front Microbiol 2018;9:461)
  • Develops after a long latency (therefore occurs in adults)
  • Most often composed of highly pleomorphic small to medium sized lymphoid cells
  • Widely disseminated and clinically aggressive
  • Clinical spectrum of HTLV-1 associated diseases is wide and includes neoplastic and nonneoplastic disorders (Clin Microbiol Rev 2010;23:577)
Terminology
  • Abbreviation: adult T cell leukemia / lymphoma (ATLL)
  • Synonyms: adult T cell leukemia, adult T cell lymphoma, adult T cell leukemia / lymphoma (HTLV-1+)
ICD coding
  • ICD-O: 9827/3 - adult T cell leukemia / lymphoma (HTLV-1+)
  • ICD-10: C91.5 - adult T cell lymphoma / leukemia (HTLV-1 associated)
Epidemiology
  • HTLV-1 virus is endemic in Southwestern Japan, the Caribbean basin, sub-Saharan Africa, South America and parts of the Middle East and Australo-Melanesia (Front Microbiol 2012;3:388)
  • Third to ninth decade, mean 58 years
  • M:F = 1.5:1
  • Transmission: requires the presence of living HTLV-1 infected cells
    1. Mother to infant (mainly by lymphocytes in breast milk) (J Pediatric Infect Dis Soc 2018;7:350)
    2. Sexual fluids
    3. Blood and blood products (not transmitted in fresh frozen plasma)
Sites
  • Widespread lymph node involvement in most
  • Systemic: spleen and extranodal sites including the skin, lungs, liver, gastrointestinal tract and central nervous system
    • Main extranodal sites: skin (involved in > 50% of cases) and peripheral blood
Pathophysiology
  • 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
Etiology
  • ATLL is uniformly causally associated with HTLV-1 infection
  • HTLV was the first human retrovirus to be identified, isolated from a patient derived T cell lymphoma cell line (Proc Natl Acad Sci USA 1980;77:7415)
  • HTLV-1 is a type C retrovirus, Deltaretrovirus genus
    • Single strand of RNA is converted into double strand of DNA in host via reverse transcriptase enzyme (Viruses 2010;2:2037)
    • Monoclonal, randomly integrates into host cell genome (Oncology 2015;89:7)
    • Infection alone is not sufficient to result in neoplastic transformation of infected cells
  • HTLV-1 can infect immature thymocytes and mature CD4+ T cells
    • Enters by cell to cell contact via 3 cellular molecules: neuropilin 1, heparan sulfate proteoglycan (HSPGs) and GLUT1 (J Virol 2006;80:6844)
  • Tax protein and HTLV-1 basic leucine zipper factor (HBZ): two major oncoproteins with key role in the development of ATLL in chronically infected individuals
    • Tax (p40): activates viral promoter, the cyclic AMP response element binding transcription factor (CREB) and nuclear factor κβ pathways (Retrovirology 2004;1:20)
    • HBZ: consistently expressed in all cases of ATLL; contributes to cellular proliferation and survival of the neoplastic clone (Retrovirology 2016;13)
  • Epigenetic alterations and hypermethylation are also involved in the development and disease progression (Nat Genet 2015;47:1304, Am J Pathol 2010;176:402)
Diagrams / tables

Contributed by Jennifer Chapman, M.D.

Differential diagnostic algorithm

Clinical features
  • 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


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
LDH = lactate dehydrogenase; *may develop later in the course of disease
Diagnostic criteria
  • Strongest support for a diagnosis of ATLL: demonstration of viral integration in the tumor cells
  • Clinical features favoring the diagnosis: appropriate patient demographic (patient derived from HTLV-1 endemic area), hypercalcemia, skin lesions and a leukemic phase
  • Histologic features favoring the diagnosis: pleomorphic T cell lymphoma, leukemic phase, CD4+ αβ type with T regulatory immunophenotype, expression of CD25
Laboratory
  • Evidence of HTLV-1 or 2 sequences at the molecular level
  • Seropositivity for anti-HTLV-1 antibody as surrogate for demonstration of monoclonal integration of virus
    • Only useful in areas with low prevalence of HTLV-1 infection
    • In areas of high HTLV-1 prevalence, viral integration must be demonstrated
  • Expression of CD25 by lymphoma cells
  • Other laboratory tests / results:
    • CBC: elevated leukocyte count and circulating neoplastic lymphocytes (leukemic phase)
    • Elevated serum LDH level reflects disease burden / activity
    • Hypercalcemia: more common in patients with acute variant; variably associated with lytic bone lesions
    • Eosinophilia and neutrophilia are common
    • Elevated soluble IL-2 receptor α chain levels in patients with aggressive ATLL
Radiology description
  • May have lytic bone lesions
    • Skull, pelvis, spine and long bones can be affected
    • Punched out lesions similar to those seen in plasma cell myeloma can be found
  • F-18 deoxyglucose PET / CT is usually positive in sites of disease activity
  • CT detects sites of nodal and extranodal disease
Prognostic factors
  • 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)
Case reports
Treatment
  • 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)
Clinical images

Images hosted on other servers:

Nodules

Gross description
  • Skin lesions have been classified as erythema, papules or nodules
  • Rare cases show tumor-like lesions or erythroderma as seen in mycosis fungoides / Sézary syndrome
  • Enlarged and effaced lymph node
Microscopic (histologic) description
  • 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
Microscopic (histologic) images

Contributed by Jennifer Chapman, M.D.

ATLL mimicking angioimmunoblastic T cell lymphoma


ATLL with Hodgkin-like cells mimicking classical Hodgkin lymphoma

ATLL mimicking mycosis fungoides


ATLL, lymphomatous type, mimicking anaplastic large cell lymphoma


Cytology description
  • ATLL cells show variable appearances
  • Irregular / polylobulated nuclei, homogeneous, condensed chromatin, small nucleoli
  • Agranular basophilic cytoplasm
  • Tumor cells in lymph nodes are frequently pleomorphic and most cases have a mixture of small to large pleomorphic cells
Peripheral smear description
  • Medium to large sized lymphocytes with multilobulated nuclei (flower cells) in the peripheral blood of acute (leukemic) ATLL
  • Slightly larger than normal peripheral blood lymphocytes with moderately condensed chromatin, absent or small nucleoli, scant slightly basophilic cytoplasm and some with multilobulated nuclei in chronic ATL
Peripheral smear images

Contributed by Jennifer Chapman, M.D.

ATLL, acute variant,
mimicking
T prolymphocytic
lymphoma



Images hosted on other servers:

Flower cells

CLL-like morphology

Positive stains
Negative stains
  • CD7, TdT, TCL1 (rare cases positive), ALK1, B cell antigens, cytotoxic molecules (rare cases positive), myeloid associated antigens
  • Most cases are CD8 negative
Flow cytometry description
Flow cytometry images

Contributed by Jennifer Chapman, M.D.

CD45

CD4

CD56

CD7

CD25



Images hosted on other servers:

CD3+, CD4+, CD25+, CD7-, CD8-

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

Images hosted on other servers:

ATLL cell

Molecular / cytogenetics description
  • Clonal integration of HTLV-1 genome can be demonstrated
  • PCR assays are positive for clonal T cell receptor gene rearrangement
  • Quantitative HTLV-1 levels
  • CCR4 mutations in ~25% of cases (Nat Genet 2015;47:1304)
  • RHOA mutations detected in ~15% of cases (Blood 2016;127:596)
  • Tumor suppressor genes are inactivated either by mutation or epigenetic silencing
  • Numerous complex chromosomal abnormalities are frequent, especially in acute and lymphomatous variants
  • Clonal chromosome abnormalities are frequent but not specific
Differential diagnosis
Board review question #1
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
Board review answer #1
D. Skin

Comment here
Board review question #2
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)
Board review answer #2
A. Dual positivity for CD4 and CD8 is uncommon in adult T cell leukemia / lymphoma

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