Angioimmunoblastic T cell lymphoma & other T Follicular Lymphomas Flashcards
Under what general category is AITL categorized ?
- T follicular helper cell lymphomas
What markers are associated with the T follicular helper cell
immunophenotype ?
- CD10, CXCL13
- BCL6, ICOS
- CXCR5
- SAP
- MAF
- CD200 (in most cases)
How does the EBV reactivation occur in AITL ?
- It is thought that EBV reactivation occurs in the context of a deregulated immune response
- This favors the expansion of both TFH and B cells
Of note:
- TGF-Beta is a mediator of FDC differentiation and proliferation
- FDCs are a source of CXCL13 and VEGF
- which drive B cell recruitment and vascular proliferation respectively
What is the definition of AITL ?
- neoplasm of mature T Follicular helper cells characterized by systemic disease and a polymorphous infiltrate involving the lymph nodes
- proliferation of high endothelial venules and FDCs is seen
- EBV positive cells - almost always present
- can be a significant part of the infiltrate
- Clinically aggressive
- usually older adults
What is the epidemiology of AITL ?
- occurs in middle aged to elderly adults
- more common in men
- accounts for 15-30% of non-cutaneous T cell lymphomas
- and 1-2% of all non-Hodgkin Lymphomas
Which cells are EBV positive in the lesions?
- the neoplastic lymphocytes are negative for EBV
- EBV is positive in background B cells
What is the localization of the lymphoma ?
- lymph node
- almost all patients present with generalized lymphadenopathy
- other common sites of involvement:
- spleen, liver, skin
- bone marrow
What is the classic clinical presentation of AITL ?
- usually has an advanced stage of disease with multiple sites
- generalized lymphadenopathy
- hepatosplenomegaly
- systemic symptoms
- polyclonal hypergammaglobulinemia
- skin rash with intense pruritis
- pleural effusion, arthritis, and ascites
What laboratory findings are often seen in AITL ?
- circulating immune complexes
- cold agglutinins
- hemolytic anemia
- positive rheumatoid factor
- anti-smooth muscle antibodies
Note: often patient’s have an immunodeficiency due to expansion of the neoplastic cells, which leads to expansion of the EBV positive cells
What are the microscopic findings of AITL ?
- can have partial or total effacement of the lymph node with sparing of the paracortical sinuses
- Cytology
- neoplastic T cells are small to medium in size
- clear to pale cytoplasm
- distinct cell membranes
- minimal atypia
- neoplastic cells often form clusters, next to HEV
- vascularity if often prominent with arborization
- Background reactive cells :
- lymphocytes, histiocytes, eosinophils, and plasma cells
- cellular density varies in each case
- sometimes amorphous interstitial precipitate is present, makes the specimen look hypocellular
What are the three patterns of AITL?
- Pattern 1: Hyperplastic follicles
- Pattern 2: Follicles with regressive features
- Pattern 3: Effaced architecture
What are the findings in pattern 1 of AITL ?
- difficult to distinguish from reactive follicular hyperplasia
- follicles have well-formed germinal centers
- but there is a lack of well-defined mantle cell cuffs
IMP: pattern 1 is difficult to differentiate from reactive follicular hyperplasia.
- Need IHC to identify T cells with TFH immunophenotype
What are the findings in pattern 2 AITL ?
- remnants of follicles remain but show regressive changes
- neoplastic cells are more readily identified in the expanded paracoretex
What are the findings in pattern 3 AITL ?
- archecture is totally effaced
- remnants of regressed follicles can be seen in the outer cortex and are displaced by the expanded paracortex
Note: progression of pattern 1 to pattern 3 has been described in cases
What can be seen in advanced cases of AITL ?
- the inflammatory component may be diminished
- the proportion of clear cells and large cells may increase
- “tumor cell rich AITL”
- IMP: this can simulate PTCL-NOS
- must demonstrate TFH immunophenotype along with expanded FDC meshworks
- neoplastic cells are aournd the FDC meshworks
- prominent reaction of epithelioid histiocytes that mimick granulomas can be seen
- Lymphoepithelioid lymphoma
What is the association of AITL and EBV ?
- variable numbers of B immunoblasts are usually present in the paracortex
- can be positive or negative for EBV
- 80-95% of cases have EBV + B cells
- expansion of B immunoblasts can be quite prominent
- AITL can be composite with or have an EBV+ DLBCL arise from it
- R-S like cells that are EBV+ can also be present and simulate HL
- rare cases these can be EBV (-)
- Plasma cells can also be abundant and obscure the neoplastic T cells
- usually polyclonal but may be monoclonal
What is the characteristic immunophenotype
for AITL ?
- express most T cell markers:
- CD3, CD2, and CD5
- note: sCD3 may be diminished by flow cytometry
- most are CD4 positive
- CD3, CD2, and CD5
- variable numbers of CD8+ T cells are present
- express TFH cell immunophenotype
- CD10, CXCL13, ICOS, BCL6 and PD-1
- IMP: this phenotype helps distinguish from atypical paracortical hyperplasia and other PTCLs
- also helpful with extranodal dissemination
Which markers are the most sensitive
and those that are most specific TFH ?
- most sensitive:
- PD1 and ICOS
- most specific:
- CXCL13 and CD10
Where are the expanded FDC meshworks located ?
- usually surrounding the HEV in the paracortex
- **outside of the follicles
- usually express CD21, CD23 and CD35
What is the normal counterpart of
AITL ?
- arises from a CD4+ TFH cell
What is the genetic profile of AITL ?
- T cell receptor genes show clonal rearrangement in 75-90% of cases
- clonal IG gene rearrangements found in 25-30% of cases
- these correspond to the EBV+ cells
- most EBV+ B cells show ongoing mutation activity while carrying hypermutated IG genes
- shows that alternative pathways allow for the survival of these forbidden mutations
What are common cytogenetic
alterations seen in AITL ?
- trisomies of:
- 3, 5 and 21
- Gain of X
- Loss of 6q
What genes are typically mutated in
AITL and which in particular is specific for AITL ?
- epigenetic modifying genes:
- IDH2 (20-30%)
- TET2 (50-80%)
- DNMT3A (20-30%)
- RHOA (small GTPase) (60-70%)
IMP: IDH2 R172 is the most specific for AITL
- the other mutated genes can be seen in other PTCL, especially those with a T follicular helper cell phenotype
What specific mutation of RHOA
is present in AITL ?
- Gly17Val-mutant - dominant negative variant
What translocation is rarely seen
in AITL ?
- t(5;9)(q33.3;q22.2)
- results in ITK-SYK gene fusion
- this fusion gene was initially identified in follicular PTCL
What are the prognostic and predictive
factors for AITL ?
- variable course, overall poor
- median survival of < 3 years
- no well defined prognostic factors have been identified
- Adverse factors
- male sex
- mediastinal lymphadenopathy
- anemia
What is the definition of
Follicular T-cell Lymphoma ?
- lymph node based neoplasm
- predominantly follicular growth pattern with TFH phenotype
- Lacks morphologic features of AITL
- no HEV proliferation
- no extrafollicular dendritic cells
What is the epidemiology of
Follicular T cell lymphoma ?
- usually seen in middle aged to older adults
- higher incidence in males
- rare neoplasm
- uncertain but likely <1% of all T cell lymphomas
What is the localization of Follicular
T cell lymphoma ?
- mostly in the lymph node
- can rare involve other organs such as:
- skin
- bone marrow
What are the clinical features of
Follicular T cell lymphoma ?
- many patients present with clinical findings similar to AITL
- hypergammaglobulinemia
- eosinophilia
- positive coombs test
- few patients can present with localized lymphadenopathy and/or no B symptoms
What are the microscopic findings of
Follicular T cell lymphoma ?
- the lymph node architecture is partially or completely effaced by nodular/follicular proliferation
- cells are intermediate
- round nuclei
- abundant (clear) cytoplasm
- two distinct growth patterns are seen:
- one that mimics follicular lymphoma
- one that mimics progressive transformation of the germinal centers
What are the findings in the follicular lymphoma pattern
in Follicular T-cell lymphoma ?
- neoplastic cells are arranged into well-delineated follicles
- lacking normal architecture of B cells
In the progressive transformation of germinal center-like
pattern of Follicular T cell lymphoma, what are the findings ?
- neoplastic cells are in well formed aggregates surrounded by small IgD+ mantle zone B cells arranged into large irregular nodules
- the interfollicular areas lack the polymorphic infiltrates and vascular proliferation characteristic of AITL
Despite lacking many features of AITL, what finding can be
seen in Follicular T helper cell lymphoma that is seen in AITL ?
- scattered immunoblasts
- Hodgkin R-S cells
- often surrounded by neoplastic T cells
Note: limited number of cases show TFH and AITL spectrum and these may represent a disease spectrum rather than separate entities.
What is the immunophenotype of T Follicular helper cell lymphoma ?
- usually CD4+ with panT cell antigen expression (CD2, CD3, and CD5)
- CD7 is usually lost
- also express multiple T follicular helper cell markers (PD1, CXCL13, BCL6, CD10 and ICOS)
- CD20+ EBV+ immunoblasts can also be seen
- HRS cells will have normal Hodgkin immunophenotype and be EBV+
- IMP: these cells should not be called CHL unless the typical CHL background is present
IMP: there is an intact FDC meshwork present (highlighted by CD21, CD23, and CD35)
What is the genetic profile of
Follicular T cell lymphoma ?
- clonal TR gene rearrangements in most cases
- IMP:
- 20% of cases carry t(5;9)(q33.3;q22.2)
- causes the ITK-SYK fusion
- translocation appears specific to TFCL, not seen in other peripheral T cell lymphomas with the exception of rare cases of AITL
What are the prognosis and predictive factors
of FTCL ?
- the lesions are rare so the clinical course is not well documented
- most studies are retrospective
- but likely aggressive course given that most patients die within 24 months
What is the definition of a Nodal peripheral T-cell lymphoma
with TFH phenotype ?
- can have some but not all the pathological features of AITL
- have the TFH immunophenotype
- no criteria for diagnosing this phenotype but ideally have at least 2/3 if not all 3 TFH markers plus CD4+
What are some of the microscopic findings of nodal
peripheral T cell lymphoma with TFH phenotype ?
- shows a diffuse infiltrate of cells
- no prominent polymorphic inflammatory background
- no vascular proliferation or FDC meshwork expansion
What do genetic studies show about
nodal peripheral T cell lymphoma with TFH phenotype ?
- share some genetic alterations with AITL
- TET2
- DNMT3A
- RHOA
These findings suggest that cases may be related to AITL and just represent a tumor rich variant. However, still not proven so best to PTCL with TFH phenotype.
