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HTLV I
and
ATLL
Blood Manifestation
A.Shirdel MD
Associated Prof. Of MUMS
Ghaem Haspital
4
Cody Crabb
Human T cell Leukemia Virus type I
(HTLV-I)
 Associated
with 2 fatal human
diseases
 Adult T cell leukemia (ATL)
– clonal malignancy of infected mature
CD4+ T cells
 Tropical spastic paraparesis/HTLV-1
associated myelopathy
– neurodegenerative disease
Human T cell Leukemia Virus
type I (HTLV-I)
• Endemic in parts of Japan, South America,
Africa, Caribbean and the Iran.
• With an estimated 10-20 million people infected worldwide
• Asymptomatic in majority of individuals with
approximately 2-5% of HTLV-I carriers
developing disease 20-40yrs post infection.
• The long clinical latency and low percentage of individuals
who develop leukemia suggest that T-cell transformation
occurs after a series of cellular alterations and mutations.
• Infects primarily CD4+ T cells.
HTLV 1 Transmission

Extended close contact (cell-associated
virus)

Sexual (60% male to female versus 1%
female to male transmission)

Blood products (screening of blood
supply since 1988)

Mother to child (breast feeding: 20%
children with seropositive mothers
acquire virus)
Epidemiology of HTLV-I
• HTLV-I infection occurs in
clusters in certain geographic
locations around the world.
• It is endemic in Southern Japan
(15-30%), Caribbean (3-6%), Papua
New Guinea and some parts of
Africa Iran
Epidemiology of HTLV-I
• Appears to be transmitted sexually
and through blood.
• Vertical transmission is thought to
play an important role in the
maintenance of virus in areas of
high endemicity.
Epidemiology of HTLV-I
• Transmission through breast milk
is implicated as a major route for
the maintenance of infection in high
prevalence areas.
• Seroprevalence of HTLV-I
increases with age
• Is twice as high in females than
males.
Epidemiology of HTLV-II
• Is particularly common in :
IV drug abusers,
• Has been found in clusters among
certain South American Indians.
Manifestations of HTLV-I
Adult T-cell leukaemia
An incubation period of 15 to 20
years have been suggested for the
development of ATL.
In the United States as a whole, the 
incidence of ATLL is approximately 0.05
cases per 100,000 population
ATLL is more common in Black Americans 
than White Americans and there is a slight
male predominance overall
The median age at diagnosis is in the sixth 
decade However, median age at diagnosis
can vary with geographic location
infection with this virus can indirectly cause
many other diseases via the induction of
immunodeficiency, such as :
chronic lung disease, chronic renal failure 
opportunistic lung infection, strongyloidiasis 
cancer of other organs, 
monoclonalgammopathy,
non-specific dermatomycosis, HTLV-I- 
associated lymphadenitis, HTLV-I uveitis
HTLV-I-associated myelopathy-tropical 
spastic paraparesis (HAM/TSP)
PATHOGENESIS
Adult T-cell lymphoma/leukemia (ATLL) is 
associated with HTLV-I infection of the
tumor clone in 100 percent of cases
In all malignant cells in an affected 
individual, the HTLV-I pro-viral
genome is incorporated into an identical
location of the genome
Whether the particular insertion location 
affects the phenotype of the cell is unclear
The long-term risk of developing ATLL following 
infection with HTLV-I in endemic areas has been
estimated to be 4 to 5 percent, usually after a
latency period of several decades
Exposure to the virus early in life increases the 
risk of eventual development of ATLL.
A shorter latency period has been noted in 
infected patients receiving treatment with
immunosuppressive agents for other reasons
The exact mechanism by which HTLV-I 
contributes to tumor development is
unknown. However, increasing evidence
suggests that the viral regulatory gene tax
(transactivating gene of the X region)
encodes an oncoprotein, named tax protein
The gene product induces cellular
proliferation, promotes cellular survival,
and impairs DNA damage repair
mechanisms

Clinical Syndromes Reported in Association with Human T-Cell Lymphotropic Virus
Types I and II (HTLV-I and HTLV-II)
HTLV-I
Adult T-cell leukemia/lymphoma
HTLV-II
Atypical hairy cell leukemia?
Large granular lymphocytic leukemia?
HTLV associated myelopathy
Myelopathy, cerebellar ataxia
Mycosis fungoides?
Mycosis fungoides?
Increased susceptibility to infections
Increased susceptibility to infections
Polymyositis
Myositis
Uveitis
Arthropathy
Sjogren's syndrome
Pulmonary syndrome, alveolitis
Infectious dermatitis
ATLL according to the most recent (WHO)
classification of lymphoid neoplasms
Defined as a peripheral T-cell neoplasm
associated with infection by the HTLV-I
Other T cell lymphomas include:
Mycosis fungoides
 T cell large granular lymphocytic leukemia
 T cell prolymphocytic leukemia
 Anaplastic large cell lymphoma
 Peripheral T cell lymphoma
 Precursor T cell lymphoblastic leukemia
( These disorders are not caused by
HTLV-1)

CLINICAL FEATURES include evidence of:
Generalized lymphadenopathy
 Hepatosplenomegaly
 Immunosuppression
 Hypercalcemia
 Lytic bone lesions
 Skin lesions

Clinical variants
Several clinical variants of ATLL have been
described:
 Acute
 Lymphomatous
 Chronic
 Smoldering

Progression from chronic and smoldering
disease to aggressive disease resembling
the acute variant eventually occurs in up
to 25 percent of cases
Acute
The most common presentation of ATLL
 Occurring in about 60 percent of cases
 Has a generally poor prognosis with
survival measured in months to a year

Patients most frequently present
with systemic symptoms:
Organomegaly
 Lymphadenopathy
 Hypercalcemia
 Elevated lactate dehydrogenase (LDH)
 Circulating malignant cells.

Common presenting signs or
symptoms include:
A high WBC is common due to the presence of
circulating lymphocytes with highly abnormal convoluted
nuclei
 Bone marrow involvement is observed in approximately
35 percent of cases.
 Generalized lymphadenopathy is seen in almost all
cases.





Hepatosplenomegaly is present in approximately 50 percent.
One-half will have hypercalcemia with or without lytic
bone lesions at presentation
Additional third will develop hypercalcemia at some point
during the course of their disease
Approximately 50 percent will have skin lesions at
diagnosis
Less common clinical features may
include:
Interstitial pulmonary infiltrates, which
may be due to pneumocystis jirovecii
pneumonia
 Central nervous system involvement with
mass lesions on imaging

Lymphomatous



Accounts for approximately
cases
Characterized by prominent lymphadenopathy
without blood involvement.
Patients frequently have an elevated
and

20 percent of
hypercalcemia.
LDH level
Prognosis is poor with a survival similar to that
of patients with the acute variant
Chronic
Approximately 15 percent of cases are a chronic variant
 Characterized by an:
 Increased white blood cell count with absolute
lymphocytosis which may be stable for months to years
 Skin lesions
 Mild lymphadenopathy.
 These patients have no hepatosplenomegaly or
hypercalcemia
 Normal or only slightly increased LDH level (less than
twice the upper limit of normal).
 This variant has a better prognosis than the acute and
lymphomatous variants with survival measured in years

Smoldering






Is least common:
Accounting for approximately 5 percent of cases
These patients are often asymptomatic
Skin and/or pulmonary lesions are common.
Normal blood lymphocyte counts with <5
percent circulating neoplastic cells and normal
calcium levels.
Median survival is more than five years.
CUTANNEUS MANIFESTATION OF
ATL
Erythematous patches
 Erythroderma
 Maculopapular
 Papules
 Plaques
 Tumors
 Ulcer

Hypercalcemia and lytic bone
lesions
In the acute variant, approximately 70 percent
of patients will have hypercalcemia at some
point in their disease course
 40 percent will have lytic bone lesions .
Hypercalcemia can be severe with calcium levels
as high as 21 mg/dL (5.25 mmol/liter).
 Signs and symptoms related to hypercalcemia
such as renal dysfunction or neuropsychiatric
disturbances may be prominent






Hypercalcemia seen in ATLL is paraneoplastic in
origin, and thought to arise from cytokines
liberated from the malignant cells.
Their exact nature is not known
The following have been proposed:
Constitutive production of parathyroid hormone
related protein (PTH-RP)
Tumor necrosis factor-beta or interleukin-1
These factors may also be the genesis of :
 Lytic bone lesions
 Increased bone turnover
 Increased serum alkaline phosphatase
Immunosuppression
Patients are immunosuppressed and at risk of
developing opportunistic infections including :
 Pneumocystis jirovecii pneumonia
 Cryptococcus meningitis
 Disseminated herpes zoster
 Infestation by and dissemination of
strongyloides stercoralis
Analysis of 818 patients with ATLL found
that 213 (26 percent ) had infection at the
time of diagnosis
 Infection were more common in patients
with the ACUTE , CHRONIC or
SMOULDERING variant than in
LYMPHOMATOUS

Of 465 patients with Acute ATLL following
infections were found at diagnosis:
 Bacterial (mostly pneumonia) in 12
percent
 Fungal (mostly cutaneous) in 8 percent
 Protozoal (mostly strongyloidiasis) in 5
percent
 Viral (mostly herpes zoster ) in 3 percent
 339 patients were without infection at
diagnosis (73 percent)
DIAGNOSIS
Is based upon a combination of :
 Characteristic clinical features
 Morphologic and immunophenotypic changes of
the malignant cells
 Confirmation of HTLV – 1
 Identification of at least five percent tumor cells
is often sufficient to make the diagnosis in acute
, chronic , or smoldering type ATLL
 In lymphomatous lesions should undergo an
excisional biopsy and molecular analysis for
HTLV 1 provirus integration.
My God!
Immunosuppression
Patients with ATLL are immunosuppressed 
and at risk of developing opportunistic
infections including pneumocystis
jirovecii pneumonia, cryptococcus
meningitis, and disseminated herpes
zoster
Severe, and often fatal, infestation by and 
dissemination of strongyloides
stercoralis is common as well
PATHOLOGY
The organs involved varies but can include the 
peripheral blood and bone marrow, lymph nodes, and
skin.
The most characteristic morphologic change seen in 
ATLL is in the peripheral blood of leukemic cases. In such
cases, medium sized lymphocytes with condensed chromatin
and bizarre hyperlobated nuclei ("clover leaf" or "flower
cells") can be found, often resembling the Sezary cells of
mycosis fungoides
Bone marrow involvement is seen in approximately 35 
percent of cases. Bone marrow infiltrates are usually
patchy, ranging from sparse to moderate.
Immunophenotype
The malignant cell of origin in ATLL is considered to be 
an HTLV-I infected mature helper (CD4+) Tlymphocyte in various stages of transformation.
At a minimum, suspected cells should be tested for 
CD3, CD4, CD7, CD8, and CD25.
Tumor cells express T-cell associated antigens (CD2, CD4, 
and CD5), but usually lack CD7
The most common immunophenotype is CD4+, 
CD25+, CD7-, and CD8Rare cases are CD4-/CD8+ or CD4+/CD8+. 
Genetics
There is no distinct molecular or karyotypic
abnormality in ATLL other than clonallyintegrated HTLV-1, which is observed in all
malignant cells .

Karyotypic analysis is generally reserved 
for patients enrolled in clinical trials. The Tcell receptor genes are clonally rearranged .
HTLV-1 infection
Practically all patients with ATLL have serologic antibodies to HTLVI. An enzyme-linked immunosorbent assay (ELISA) is the most
frequently used screening test, using antigens prepared from whole
virus lysate or by recombinant technology.

Western blotting (WB) is normally used for confirmatory testing. WB
also distinguishes between infection with HTLV-I and the less
pathogenic HTLV-II.

Polymerase chain reaction (PCR) based testing to detect proviral
DNA in tumor cells should be performed in the rare instance where
serology is negative but suspicion for ATLL is high. This test will also
differentiate HTLV-I from HTLV-II infection.

A definite diagnosis of ATL is made by 
documenting the presence of HTLV-I
proviral DNA in the DNA of tumour cells.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of ATLL includes 
other T cell lymphoid malignancies such as
cutaneous T cell lymphoma, Tprolymphocytic leukemia (T-PLL),
anaplastic large cell lymphoma, and
angioimmunoblastic T-cell
lymphoma. Some cases of ATLL can
resemble Hodgkin disease morphologically
Cutaneous T cell lymphoma
ATLL can be difficult to distinguish from forms of cutaneous T cell
lymphoma (CTCL), such as mycosis fungoides and sezary
syndrome.

Both of these disorders can have cutaneous manifestations with
malignant T cells circulating in the peripheral blood and
findings on skin biopsy that are practically identical
morphologically

They can also have a similar immunophenotype. Both are
CD4+ and CD7-

While ATLL has a more uniform, strong positivity for CD25, CD25
positivity is more variable in CTCL.
The key differentiating feature is the presence of HTLV-I in
the malignant cells of ATLL


T-prolymphocytic leukemia
Immunophenotype can help distinguish this 
disorder from ATLL.
As with ATLL, T-PLL is CD4+. However, unlike 
ATLL, T-PLL is CD7+ and CD25HTLV-I is not incorporated into the genome of 
the malignant cell and more than 80 percent of
patients will have genetic abnormalities,
usually an inversion of chromosome 14
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL) is another T-cell lymphoid neoplasm
which primarily involves the lymph nodes and skin but can
demonstrate circulating malignant cells.

Cell morphology is varied and the immunophenotype is CD4+ and 
CD7- much like ATLL. Immunohistochemistry staining can be of help
since ALCL has strong, uniform expression of CD30
The diagnosis of ALCL can be confirmed in many cases by demonstrating an 
ALK1 gene rearrangement or expression of the Alk-1 protein, neither of
which can be found in ATLL.
However, the cutaneous variant of ALCL is less likely than the 
systemic variant to demonstrate ALK1 positivity. In addition, HTLV-I
is not incorporated into the genome of the malignant cell in ALCL
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