Nodal Peripheral T-Cell Lymphomas

Question 1

Four major groups of Anaplastic Large Cell Lymphoma

Answer 1

1. AKL+
2. ALK -
3. Primary cutaneous
4. Breast implant-associated

Question 2

Of the types of ALCL, which are systemic and which are localized?

Answer 2

ALK+ NPTCL and ALK- NPTCL are systemic.

Primary cutaneous and breast implant-associated are localized.

Question 3

General principles of nodal ALCL

Answer 3

Effacement of the lymph node by a proliferation of large neoplastic cells, which may spare residual reactive follicles.

At least some neoplastic cells show Hallmark cell features.

Infiltration pattern may be diffuse, lymphohistiocytic, small cell, or Hodgkin-like.

Most are diffusely CD30+, CD4+, and positive for granzyme/perforin/TIA-1. Loss of CD3 is common.

Question 4

Answer 4

ALK Positive ALCL

The morphology of ALK positive is that of the “classical” ALCL.

Harbors chromosomal rearrangements in ALK on 2p23.

The location of ALK positivity depends on the underlying translocation:

NPM1::ALK - Nuclear and cytoplasmic (most common)
CLTC::ALK - Granular cytoplasmic
MSN::ALK - Membranous
Other partners (TPM3, ATIC, TFG, TPM4, MYH9, etc etc): Cytoplasmic

Additional molecular alterations may include TP53 and NOTCH1 alterations.

If staining is equivocal, proceed to FISH for diagnosis.

IHC: CD30+, CD4+, Cytotoxicity panel+, ALK+ (see above patterns)

Question 5

Answer 5

ALK Negative ALCL with DUSP22 rearrangement

Unlike “classical” ALK+ ALCL, the cells of ALK negative ALCL tend to be relatively smaller and to contain characteristic “doughnut cells” with nuclear pseudoinclusions. Classical Hallmark cells are also present.

Characteristically carry a DUSP22 rearrangement rather than an ALK rearrangement.

IHC: CD30+, CD4+, Lef1+, CCR8+, Cytotoxicity panel neg, ALK neg, pSTAT3 (Y705) negative

Question 6

ALK Negative ALCL with p63 rearrangement

Answer 6

Makes up the minoritry of ALK negative ALCLs (5-8%). These translocations are also found in PTCL-nos, mycosis fungoides, and DLBCL.

Highly aggressive compared to other ALCLs.

IHC: CD30+, CD4+, Cytotoxicity panel+, ALK-, p63+ (highly sensitive, but not specific)

Question 7

Triple negative ALCL

Answer 7

ALCL negative for rearrangements in ALK, DUSP22, and p63.

Question 8

Gold standard for subtyping ALK negative ALCL

Answer 8

FISH

Question 9

ALCL Subtyping Algorithm

Answer 9

Question 10

ALCL treatment algorithm

Answer 10

Question 11

Answer 11

ALK+ LBCL

An important differential diagnosis for ALCLs. Note the plasmablastic morphology in ALK+ LBCL.

IHC: CD30 negative, CD138+, CD38+, Ig light chain+.

Remember, ALK+ LBCL is a B cell lymphoma and ALCL is a T cell lymphoma!

Question 12

Answer 12

ALK+ Histiocytosis

An important differential diagnosis for ALCL. Some Touton-type giant cells are usually also present.

IHC: ALK+, CD68+, CD163+, CD14+, CD4+

Question 13

Marker for breast implant-associated anaplastic large cell lymphoma

Answer 13

CAIX

Question 14

Subtypes of nodal T-follicular helper cell lymphoma

Answer 14

Angioimmunoblastic
Follicular
NOS

Question 15

Answer 15

Nodal T-follicular helper cell lymphoma, Angioimmunoblastic-type

Effaces the normal architecture. Neoplastic cells are small-to-medium lymphocytes with pale, clear cytoplasm. Proliferation of arborizing HEVs and FDCs is classic. Immunoblasts are present, sometimes with RS-like features. These immunoblasts retain the B cell program and may be EBV+.

IHC: CD4+, CD2+, CD3+, CD5+, CD7 +/-, positive for at least two TFH markers (CD10, BCL6, CXCL13, PD1, ICOS)

Question 16

Answer 16

Nodal T-follicular helper cell lymphoma, Follicular-type

Predominantly follicular pattern lacking the classic features of AITCL. Lymph node architecture is effaced by small-to-medium lymphocytes with pale, clear cytoplasm, expressing TFH markers. EBV-positive immunoblasts are frequently found.

Two distinct histologic patterns:
1. Follicular lymphoma-like
2. Progressive transformation of germinal centers-like

IHC: CD4+, CD2+, CD3+, CD5+, CD7 +/-, positive for at least two TFH markers (CD10, BCL6, CXCL13, PD1, ICOS)

Question 17

The neoplastic cells are positive for CD10 and ICOS.

Answer 17

Nodal T-follicular helper cell lymphoma, NOS

Lymph node architecture is effaced by small-to-medium lymphocytes with pale, clear cytoplasm, expressing TFH markers. EBV-positive immunoblasts are frequently found. Cells lack follicular architecture or the hallmark features of angioimmunoblastic TfH cell lymphoma.

IHC: CD4+, CD2+, CD3+, CD5+, CD7 +/-, positive for at least two TFH markers (CD10, BCL6, CXCL13, PD1, ICOS)

Note: This is a major differential diagnosis for peripheral T-cell lymphoma, NOS – all you need to do is demonstrate TfH phenotype to make the conversion.

Question 18

Molecular features of nodal T-follicular helper cell lymphomas

Answer 18

All three subtypes share similar molecule features:

Frequent mutations in RHOA, TET2, DNMT3A, and IDH2.

A recurrent translocation, ITK::SYK, is frequently found in the follicular subtype (around 40%) and less commonly in the angioimmunoblastic subtype.

Question 19

RHOA G17V

Answer 19

RHOA G17V lacks canonical GTP-binding capacity and specifically binds to VAV1, augmenting its adaptor function and accelerating TCR signaling.

This is a very common recurrent mutation, occuring in the majority of all three subtypes of nodal TfH cell lymphoma.

Question 20

TfH markers

Answer 20

High sensitivity, low specificity: ICOS, PD1
High specificity, low sensitivity: CD10, CXCL13
Other: BCL6, SAP1, CXCR5

Question 21

Answer 21

Primary nodal EBV-positive T/NK-cell lymphoma

As an EBV positive NK/T cell lymphoma, the demographics and geographic distribution are similar to those of extranodal NKTCL, nasal type. Patients who acquire this variant are more likely to have a prior predisposing immunodeficiency.

Shows effacement of the lymph node architecture by a proliferation of medium-to-large-sized lymphocytes. Interfollicular infiltration of neoplastic cells may alsao be seen. Neoplastic cells prototypically exhibit centroblastic morphology, resembling DLBCL.

Unlike in extranodal NK/T cell lymphoma, angiocentric infiltration and necrosis are rare.

Usually this lymphoma is of T cell lineage by TCR protein expression or clonal TCR gene rearrangement, however about 20% or less are of NK cell origin.

IHC: Positive for pan-T-cell markers, positive for cytotoxicity markers, usually CD4 - / CD8+, frequent loss of CD5. ISH for EBV is positive (by definition), usually with type 2 latency pattern.

Prognosis is. . . even worse than extranodal NKTCL. Median survival is 2.5 to 8.9 months.

Question 22

The neoplastic cells are negative for all TfH markers.

Answer 22

Peripheral T-cell lymphoma, NOS

Heterogeneous category of nodal and extra-nodal lymphomas that cannot be assigned to another PTCL category. It is therefore a diagnosis of exclusion.

Nodal PTCL-NOS may show a pattern of paracortical or diffuse involvement. Epithelioid histiocytes may be numerous (so-called, Lennert lymphoma). Occasional cases contain scattered RS-like or EBV-positive immunoblasts, which are often CD30+.

These lymphoms are subtyped into groups based on gene expression:
GATA3+ - Shows a Th2-like gene expression profile. Defined as GATA3+CCR4+ lymphomas.
TBX21+ - Shows a Th1-like expression profile, EOMES, and target genes like IFNG and IL2RB. Defined as TBX21+CXCR3+ lymphomas.

IHC: Abberant loss or diminished expression of one or more pan-T-cell markers is common. Predominantly CD4+ / CD8 neg. By definition, TfH markers are negative (one positive is allowed). Cytotoxic markers are positive in a subset (often cases that are CD8+ or CD56+).