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Hematopathology WHO T cell Neoplasms > Angioimmunoblastic T cell lymphoma & other T Follicular Lymphomas > Flashcards

Angioimmunoblastic T cell lymphoma & other T Follicular Lymphomas Flashcards

1
Q

Under what general category is AITL categorized ?

A
  • T follicular helper cell lymphomas
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2
Q

What markers are associated with the T follicular helper cell

immunophenotype ?

A
  • CD10, CXCL13
  • BCL6, ICOS
  • CXCR5
  • SAP
  • MAF
  • CD200 (in most cases)
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3
Q

How does the EBV reactivation occur in AITL ?

A
  • 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
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4
Q

What is the definition of AITL ?

A
  • 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
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5
Q

What is the epidemiology of AITL ?

A
  • 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
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6
Q

Which cells are EBV positive in the lesions?

A
  • the neoplastic lymphocytes are negative for EBV
  • EBV is positive in background B cells
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7
Q

What is the localization of the lymphoma ?

A
  • lymph node
    • almost all patients present with generalized lymphadenopathy
  • other common sites of involvement:
    • spleen, liver, skin
    • bone marrow
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8
Q

What is the classic clinical presentation of AITL ?

A
  • 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
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9
Q

What laboratory findings are often seen in AITL ?

A
  • 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

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10
Q

What are the microscopic findings of AITL ?

A
  • 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
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11
Q

What are the three patterns of AITL?

A
  • Pattern 1: Hyperplastic follicles
  • Pattern 2: Follicles with regressive features
  • Pattern 3: Effaced architecture
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12
Q

What are the findings in pattern 1 of AITL ?

A
  • 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
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13
Q

What are the findings in pattern 2 AITL ?

A
  • remnants of follicles remain but show regressive changes
  • neoplastic cells are more readily identified in the expanded paracoretex
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14
Q

What are the findings in pattern 3 AITL ?

A
  • 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

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15
Q

What can be seen in advanced cases of AITL ?

A
  • 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
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16
Q

What is the association of AITL and EBV ?

A
  • 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
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17
Q

What is the characteristic immunophenotype

for AITL ?

A
  • express most T cell markers:
    • CD3, CD2, and CD5
      • note: sCD3 may be diminished by flow cytometry
    • most are CD4 positive
  • 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
18
Q

Which markers are the most sensitive

and those that are most specific TFH ?

A
  • most sensitive:
    • PD1 and ICOS
  • most specific:
    • CXCL13 and CD10
19
Q

Where are the expanded FDC meshworks located ?

A
  • usually surrounding the HEV in the paracortex
    • **outside of the follicles
  • usually express CD21, CD23 and CD35
20
Q

What is the normal counterpart of

AITL ?

A
  • arises from a CD4+ TFH cell
21
Q

What is the genetic profile of AITL ?

A
  • 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
22
Q

What are common cytogenetic

alterations seen in AITL ?

A
  • trisomies of:
    • 3, 5 and 21
  • Gain of X
  • Loss of 6q
23
Q

What genes are typically mutated in

AITL and which in particular is specific for AITL ?

A
  • 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
24
Q

What specific mutation of RHOA

is present in AITL ?

A
  • Gly17Val-mutant - dominant negative variant
25
Q

What translocation is rarely seen

in AITL ?

A
  • t(5;9)(q33.3;q22.2)
  • results in ITK-SYK gene fusion
  • this fusion gene was initially identified in follicular PTCL
26
Q

What are the prognostic and predictive

factors for AITL ?

A
  • variable course, overall poor
  • median survival of < 3 years
  • no well defined prognostic factors have been identified
  • Adverse factors
    • male sex
    • mediastinal lymphadenopathy
    • anemia
27
Q

What is the definition of

Follicular T-cell Lymphoma ?

A
  • lymph node based neoplasm
  • predominantly follicular growth pattern with TFH phenotype
  • Lacks morphologic features of AITL
    • no HEV proliferation
    • no extrafollicular dendritic cells
28
Q

What is the epidemiology of

Follicular T cell lymphoma ?

A
  • usually seen in middle aged to older adults
  • higher incidence in males
  • rare neoplasm
    • uncertain but likely <1% of all T cell lymphomas
29
Q

What is the localization of Follicular

T cell lymphoma ?

A
  • mostly in the lymph node
  • can rare involve other organs such as:
    • skin
    • bone marrow
30
Q

What are the clinical features of

Follicular T cell lymphoma ?

A
  • 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
31
Q

What are the microscopic findings of

Follicular T cell lymphoma ?

A
  • 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
32
Q

What are the findings in the follicular lymphoma pattern

in Follicular T-cell lymphoma ?

A
  • neoplastic cells are arranged into well-delineated follicles
  • lacking normal architecture of B cells
33
Q

In the progressive transformation of germinal center-like

pattern of Follicular T cell lymphoma, what are the findings ?

A
  • 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
34
Q

Despite lacking many features of AITL, what finding can be

seen in Follicular T helper cell lymphoma that is seen in AITL ?

A
  • 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.

35
Q

What is the immunophenotype of T Follicular helper cell lymphoma ?

A
  • 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)

36
Q

What is the genetic profile of

Follicular T cell lymphoma ?

A
  • 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
37
Q

What are the prognosis and predictive factors

of FTCL ?

A
  • 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
38
Q

What is the definition of a Nodal peripheral T-cell lymphoma

with TFH phenotype ?

A
  • 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+
39
Q

What are some of the microscopic findings of nodal

peripheral T cell lymphoma with TFH phenotype ?

A
  • shows a diffuse infiltrate of cells
  • no prominent polymorphic inflammatory background
  • no vascular proliferation or FDC meshwork expansion
40
Q

What do genetic studies show about

nodal peripheral T cell lymphoma with TFH phenotype ?

A
  • 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.

Hematopathology WHO T cell Neoplasms (14 decks)

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