T-cell LGL Leukemia Flashcards
What is the definition of T-cell
large granular lymphocytic leukemia?
- heterogeneous disorder characterized by persistent (> 6 months) increase in the number of peripheral blood LGLs.
- usually 2-20 x 10^9/L
- no clearly identified cause for them
What is the epidemiology of T- LGL leukemia ?
- accounts for 2-3% of mature, small lymphocytic leukemias
- equal male to female ratio with no clearly defined age peak
- but it is RARE in patients < 25 years old
- most cases occur in ages 45-75
What is the etiology of
T-cell LGL leukemia ?
- pathophysiology of this is not well understood
- clonal LGLs retain many phenotypic and functional properties of cytotoxic T lymphocyte effector memory cells
- theory:
- arises in the setting of sustained immune stimulation
- absence of homeostatic apoptosis (express high levels of FAS and FASL)
- FASL levels are elevated in sera of many patients
- may be cause of the neutropenia
Other than the FAS/FASL pathway, what
other pathways are possibly altered in T-LGL leukemia?
- MAPK
- PI3K/ATK
- NF-KappaB
- JAK/STAT
- STAT3
- about 1/3 of the cases carry a STAT3 mutation
- rarely mutations of SH2 domain of STAT5B are observed
Note: it is possible that the T-LGLs start as an immune response to a chronic, persistent stimulus with eventual clonal selection
What is the localization of T-LGL leukemia?
- peripheral blood
- bone marrow
- liver
- spleen
- rare involvement
- skin
- lymph nodes
What are the key clinical features of T-LGL leukemia?
- generally an indolent clinical course
- present with:
- severe neutropenia (sometimes anemia)
- thrombocytopenia is rare
- lymphocyte count is 2-20 x10^9/L
- if the LGL count is less but other criteria are met then this is consistent
- could be just a smaller clone
What can be a potential pitfall
in the diagnosis of T-LGL leukemia?
- the development of oligoclonal T-cell populations following allogeneic bone marrow transplant can occur during lymphocyte reconstitution
Note: red blood cell hypoplasia has been reported in T-LGL leukemia
What are the frequent clinical findings on lab
or physical exam with T-LGL leukemia?
- moderate splenomegaly is the key finding
- Rheumatoid arthritis and autoantibodies are often associated with this
- also: circulating immune complexes and hypergammaglobulinemia are often seen as well
IMP: oligoclonal and monoclonal expansions can be seen in a variety of situations.
- ex: form of PTLD, associated with B cell malignancies particularly hairy cell leukemia and CLL, also following immunotherapy
What association has been seen
with CD4+ T-LGL populations?
- they are often associated with hematological malignancies
What is the prognosis or outcome that has
been seen in T-LGL leukemia?
- morbidity and mortality are mostly due to cytopenias
- no difference in survival has been seen in patients with STAT3 mutations
- but they do seem to be associated with more symptomatic disease and shorter treatment failure
- STAT5B
- associated with more aggressive disease
What are the microscopic findings
of T-LGL leukemia ?
- LGLs
- predominant lymphocyte in the blood and bone marrow
- moderate to abundant cytoplasm with course azurophilic granules
- these contain perforin and granzyme B
- granules have an ultrastructural appearance: parallel tubular arrasy
- Bone marrow
- normo, hypo to sometimes hypercellular despite the cytopenias
- granulocytes show left shifted maturation
- mild to moderate reticulin fibrosis is present
- involvement is usually < 50%
- interstitial and intrasinusoidal infiltrates that are difficult to see
- Nodular, reactive lymphoid aggregates are often seen (B cells surrounded by CD4+ T cells)
What is the morphology of splenic
involvement by T-LGL leukemia?
- infiltration and expansion of the red pulp cords and sinuses
- the often hyperplastic white pulp is spared
What is a variant of T-LGL leukemia?
- morphologically look like LGLs but have an NK-cell immunophenotype
- negative for sCD3 and TCR expression
- classified with the NK-cell disorders
What is the immunophenotype of
T-LGL leukemia ?
- mature
- positive for: CD2, CD3, CD8 and CD57
- generally alpha-beta….but can occasionally see gamma-delta
- abnormally decreased CD5 and CD7 is common in T-LGL leukemia
- >80% of cases express CD16 and CD57
- positive for cytotoxic effector proteins: TIA1, Granzyme B, and Granzyme M
- IMP
- KIRS can be expressed in 50% of cases
- generally a uniform expression which is a surrogate for clonality
- CD56 expression is uncommon
- KIRS can be expressed in 50% of cases
What is the cell of origin
for T-LGL leukemia ?
- common type
- subset of CD8+ alpha beta T cells
- less common type
- subset of gamma delta T cells
