10/21/2019...2019/10/03 · 10/21/2019 1 2019 updates on aggressive t-cell lymphomas alejandro a....

10/21/2019

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2019Updates on Aggressive T-

cell LymphomasAlejandro A. Gru, M.D.

Associate Professor of Pathology &

Dermatology

Dermatopathology Division and

Fellowship DirectorUniversity of Virginia

Charlottesville, VA

[email protected]

Conflicts of Interest disclosure:

- Seattle Genetics: consultant, advisory board in CTCL, lecturer (SOLAR program)- Bristol-Meyer Squibb: consultant, advisory board- Takeda: Speaker- Innate Pharma: Consultant- Stemline Therapeutics: consultant

Objectives

• Understand common clinical and histopathologic findings in primary cutaneous aggressive T-cell lymphomas

• Introduce prospective changes to the WHO classification of skin lymphomas

• Understand common clinical and histopathologic findings in systemic T-cell lymphomas with skin dissemination

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Cutaneous T-cell lymphomas

• Mycosis Fungoides

• Sézary syndrome

• Primary cutaneous CD30-positive lymphoproliferative disorders

– Lymphomatoid papulosis (LyP)

– Cutaneous anasplastic large cell lymphoma (C-ALCL)

• Subcutaneous panniculitis-like T-cell lymphoma

• Primary cutaneous γδ T-cell lymphoma

• Primary cutaneous CD8+ aggressive epidermotropiccytotoxic T-cell lymphoma

• Primary cutaneous small to medium size CD4+ T-cell lymphoma

Things change… WHO 2017…

• Hydroa vacciniforme-like lymphoma and HV changed to LPD

• Lymphomatoid papulosis new subtypes

– Type D

– Type E

– DUSP22/IRF4

• Primary cutaneous γδ T-cell lymphoma now permanent category

• Primary cutaneous CD4+ small/medium T-cell LPD

Aggressive T-cell Lymphomas

• Primary Cutaneous T-cell lymphomas

– Sezary syndrome

– Aggressive epidermotropic CD8+ cytotoxic cutaneous T-cell lymphoma

– Primary Cutaneous Gamma-Delta T-cell Lymphoma

– Peripheral T-cell lymphoma, NOS

• Systemic T-cell lymphomas with skin involvement

– Adult T-cell leukemia/lymphoma

– Angioimmunoblastic T-cell lymphoma

– Anaplastic large cell lymphoma

– T-cell prolymphocytic leukemia

– Extranodal NK/T-cell lymphoma

– T lymphoblastic lymphoma

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A correct lymphoma diagnosis requires an adequate clinical correlate…

Sézary syndrome

• Rare subtype of CTCL, closely related to MF

• Triad:– Exfoliative erythroderma (>80%

BSA)

– Lymphadenopathy

– PBL involvement by Sézary cells (>1000 cells/ml)

• Derived from mature skin-homing central memory T-cells

• 50-60 years (1.55:1)

• Clinical features:– Erythroderma, ectropion,

palmoplantar scaling, onychodystrophy

– Sometimes sparing of skin folds

– Infections

• Survival: 2.5 – 4.6 years

SS

Courtesy of Dr. Ellen Kim. U. Pennsylvania

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SS - Histopathology

• Similar to MF– Atypical small to medium

sized lymphocytes with cerebriform nuclei

– Epidermotropism <<< prominent than in MF

– Pautrier microabscesses are rare

– LCT can also occur

• Immunophenotype– Invariably CD4+

– Loss of CD7 is less frequent when compared to MF

– Invariable loss of CD26

– PD-1+

• Flow cytometry criteria:– CD4:CD8 > 10

– %CD4/CD26- > 40%

– %CD4/CD7- > 30%

– KIR3DL2 (MORE SPECIFIC), BUT LESS SENSITIVE

– B2 > 1,000 CELLS/UL

– B1 > 5% LYMPHOCYTES (NOT B2)• B1A: CLONE NEGATIVE

• B1B: CLONE POSITIVE

SS

CD3 CD7

CD4 CD8

SS

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SS – Flow cytometry

SS

• Median survival = 4 years

• Presence of skin clone

– Blood

– Skin

• Preceding diagnosis of MF

• LDH

SS with LCT

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SS with LCT

CD3 CD7

SS with LCT

CD4 CD30

Aggressive epidermotropic CD8+ cytotoxic cutaneous T-cell lymphoma

• AETLC is now a permanent category in revised WHO

• Originally described by Berti in 1999 (Berti’s lymphoma)

• <1% of CTCLs

• Male predominance, mean age 54.5 (27-87)

– Very rare pediatric cases reported

• Few cases reported in the setting of HIV and HTLV infection, and immunosupressants (e.g. adalimumab)

• Clinical presentation: – Widespread plaques, papulonodules and tumors

– Other morphologies: annular lesions, pustules, PG-like lesions, maculo-papular eruption of face, hands and feet

– Frequent mucosal, acral and genital involvement

– Short duration of clinical onset of the lesions

• Preceding patch-plaque history of MF is not seen in AETCL

• Median survival 12 months (n=18 cases); others 5 year survival 32%

• Treatment: systemic chemotherapy, bone marrow transplant

• Subset of cases had chronic path/plaque disease >6 months

Gru AA, Schaffer A. Hematopathology of the Skin. LWW 2016

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AETCL

AETCL

Histopathology

• Hallmark of this entity is striking pagetoid epidermotropism of CD8+ T-cells

• Pautrier microabscesses are not common

• Adnexal structures frequently involved

• Epidermal changes

– Hyperkeratosis, acanthosis, ulcer/erosions, atrophy

• Numerous necrotic keratinocytes and spongiosis can lead to blister formation

• Lymphoid infiltrate:

– Pleomorphic, small to medium sized

– Dermal nodular, interstitial or diffuse pattern

– Extension into adipose tissue is common

• Patterns typical of cytotoxic lymphomas:

– Epidermal and dermal necrosis, ulceration

– Karyiorrhexis

– Angiodestruction (less prominent when compared to γδ CTCL)

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AETCL

AETCL

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AETCL

AETCL – Subcutaneous involvement

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AETCL – interstitial pattern

AETCL - Immunophenotype

• IHC: CD3+, CD8+, BF1+, CD4-, EBV-

– At least one cytotoxic marker (but always recommend to do at least 2)

• TIA-1, Granzyme B, Perforin

• Ki67 very high (>75%)

• CD45RA+, CD45RO-, TCR-gamma negative

• Variable staining for CD2, CD5, CD7, CD56

• CD30 negative

• TCR gene rearrangement positive

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CD3 CD8


Granzyme B TIA-1


BF1

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Array‐based CGH of primary cutaneous CD8+ aggressive

epidermotropic cytotoxic T‐cell lymphoma

Genes, Chromosome and Cancer 2018

Primary cutaneous γδ T-cell lymphoma (PCGDTL)

• PCGDTL is a rare subtype of cytotoxic CTCL characterized by epidermal and/or subcutaneous involvement with γδ lymphoma cells.

• <1% of CTCL, ages 50-60

• Small subset (<5%) associated with EBV

• Clinical: numerous and sometimes solitary dermal or panniculitic plaques with frequent ulceration, necrosis and crust

– Lower extremities, trunk, arms, face

– Lesions can mimic MF

– +/- constitutional symptoms

– Occasional association with hemophagocytosis(worse prognosis)

• Survival: 0-34% at 5 years; 19.9%, median survival 31 months (Guitart et al, Am J Surg Pathol 2012)

PCGDTL

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PCGDTL

• Histopathology:

– Malignant infiltrate in the epidermis, dermis and adipose tissue

• Dermis is epicenter

– Perivascular, periadnexal, lichenoid, interstitial, nodular and diffuse patterns can be seen

– Karyorrhexis, necrosis and emperipolesis can be noted

– Similar to SPTCL, lobular panniculitis with ‘rimming’ of malignant lymphocytes

– Marked epidermotropism, simil to PR or AETCL (also epidermal changes)

– Angiocentricity and angiodestruction are common

– Infiltrate can be monotonous or pleormorphic (small, medium and large lymphoma cells)

– Some cases can look like MF

• Immunophenotype:

– CD3+,CD2+, γM1+,BF1-, TIA-1+, Granzyme B+,CD56+

– CD4 and CD8-,CD5-,CD45RA-,CD7-

– CD30-

– EBV- (<5% is positive) Am J Surg Pathol 2012

PCGDTL

PCGDTL

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PCGDTL

PCGDTLC

PCGDTL

CD3 CD56

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PCGDTL

CD4 CD8

PCGDTL

BF1 TCR γδ

Kaplan and Meier plots of patients with cutaneous T-cell lymphoma.(A)

Survival of individuals with cutaneous T-cell lymphoma according to T-

cell–receptor immunophenotype.

Jorge R. Toro et al. Blood 2003;101:3407-3412

©2003 by American Society of Hematology

𝛂𝛃

𝛄𝛅Subq

Epid

Subq

Epid

𝛂𝛃

𝛄𝛅

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PCGDTL

• 20 cases from MD Anderson Cancer Center

• 13 cases with Epidermotropic forms and 7 cases with subcutaneous

• Many with history of patch-plaque disease

• 19.2 months vs 10 months

• EGDTL less frequently CD56+ compared to SCGDTCL

Am J Surg Pathol. 2017 .

TCRB

TCRGTCRB

TCRG

Recognizing phenotypic switch

Am J Dermatopathol 2016

Not everything with 𝛾𝛿 T-cells is

bad…

TCRgamma

DIAGNOSIS: PLC WITH PROLIFERATION OF 𝛾𝛿 T-cells

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Reactive gamma-delta T-cells -Lyme

Reactive gamma-delta T-cells -Lyme

PCGDTCL have different cell of origins depending on the location of the infiltrate

TRDV1 TRDV2

0

50

100

Perc

ent of sam

ple

s

E/D

Panniculitic

! chain usage

0.01999.7

0.310.046

98.9 1.02

Epidermis Subcutaneous adipose

V! 1 V! 2

0.0

0.5

1.0

! chain usage

Fre

quency (

%)

of "

! T

cells

Epidermis

Dermis

Subcutaneous Adipose

99.7

0.037

0.21

Dermis

A B C

D E F

PB-Vδ1

PE

-Vδ

2

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The location also is associated with different clinical profiles

0 50 100 150 2000

50

100

Months Elapsed

% S

urv

ival

Epidermal+/- Dermal

Panniculitic

E/D

Panni

culitic

0

20

40

60

80

100P

reva

lence

(%

)

Tumor Lesions

!

E/D

Panni

culitic

0

25

50

Pre

vale

nce

(%

)

Lymph Node Involvement

0 20 40 60 80 1000

50

100

Months Elapsed

% S

urv

ival

Epidermal/Dermal

Panniculitic

E/D

Panni

culitic

0

20

40

60

80

100

Pre

vale

nce

(%

)

!

B Symptoms

E/D

Panni

culitic

0

10

20

30

40

Pre

vale

nce

(%

) ! !

HLH

E/D

Panni

culitic

0

20

40

60

80

100

Pre

vale

nce

(%

)

UlcerationsA B C D

F

H I J

E

0 100 200 3000

50

100

Months Elapsed

% S

urv

ival

Epidermal

Dermal

Panniculitic

E/D

Panni

culitic

0

10

20

30

40

Pre

vale

nce

(%

)

Visceral Spread

E/D

Panni

culitic

0

50

100

Pre

vale

nce

(%

)

Cytotoxic MarkersG

K

L

Genetic landscape of PCGDTL

MAPK

Signaling

MYC

Signaling

JAK/STAT

Signaling

Chromatin

Modification

Other

0

2000

P74L

Myc amino-terminal region HLH

G34R

Myc amino-terminal region HLH

G12DR41S

Q61HD119N

Ras family

R430CP702A

STAT_int STAT_alpha STAT_bind SH2

D661V

STAT_int STAT_alpha STAT_bind SH2

MYC

MYCN

KRAS

STAT5B

STAT3

0.0 0.2 0.4 0.6 0.8 1.0

22q22p21q21p20q20p19q19p18q18p17q17p16q16p15q15p14q14p13q13p12q12p11q11p10q10p

9q9p8q8p7q7p6q6p5q5p4q4p3q3p2q2p1q1p

Frequency of amplification

Chro

mosom

e a

rm

Epidermal/Dermal

0.0 0.2 0.4 0.6 0.8 1.0




Chro

mosom

e a

rm

Panniculitic

0.0 0.2 0.4 0.6 0.8 1.0



Frequency of deletion

Chro

mosom

e a

rm

Epidermal/Dermal

0.0 0.2 0.4 0.6 0.8 1.0




Chro

mosom

e a

rm

Panniculitic

0.0 0.2 0.4 0.6 0.8

16p13.3

9p21.3

1p36.11

Epidermal/Dermal


0.0 0.2 0.4 0.6 0.8

16p13.3

9p21.3

1p36.11


Panniculitic

0.0 0.2 0.4 0.6 0.8 1.0

22q12.317q24.2

17q1217p13.217p13.116p11.215q11.214q24.2

12q24.1211p15.58q13.17q36.16q23.22q12.21q23.3

1p36.331p36.22

1p35.2


Epidermal/Dermal

0.0 0.5 1.0

22q12.317q24.2

17q1217p13.217p13.116p11.215q11.214q24.2

12q24.1211p15.58q13.17q36.16q23.22q12.21q23.3

1p36.331p36.22

1p35.2


Panniculitic

A

B

C

D

E

F

** * * *

Peripheral T-cell lymphoma, NOS

• Very uncommon diagnosis to make

– MUST NOT USE THE TERM PTCL, NOS FOR A SKIN LYMPHOMA UPON THE FIRST TIME OF DIAGNOSIS

• Basket category – current WHO is limiting more and more the diagnosis

• Primary cutaneous PTCL is no systemic diagnosis after 6 months

• Survival 16% at 5 years

• Pathology: mild epidermotropism, angiotropism and neurotropism. Usually medium sized pleomorphic cells.

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CD3 CD20


T-cell prolymphocytic leukemia

• Rare aggressive mature T-cell leukemia (2%) in older individuals

• High lymphocytosis without hypercalcemia or nodal disease

• Skin involvement in 20-50% of patients

– Facial erythema, periorbital edema, conjunctival injection

– Linear skin nodules with petechial / purpuric quality

• Very poor prognosis


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• T-PLL lacks epidermotropism and shows a perivascular and interstitial pattern

• On the skin, prolymphocytes can show a large appearance and cerebriform morphology

• Both ATLL and T-PLL are angiotropic and pleomorphic

• Immunophenotype

– CD2+,CD3+,CD7+

– CD4+(65%), CD4+CD8+(21%), CD8+(17%)

– High levels of CD52

• Genetics: Inversion (14)(q11;q32) or t(14;14) in 2/3 of cases



CD3 CD7

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Anaplastic large cell lymphoma

• Two variants: ALK+ and ALK-– New subtypes (DUSP22 and TP63

translocation)

• ALK+ 10-30% of all pediatric NHL– After insect bites

– Some isolated examples limited to skin

– 26% cutaneous involvement

• ALK-: 50-60% of ALCL– Older patients

– 17% skin involvement

• Histology: different varians, hallmark cells

• IHC: CD30+, ALK+ – Loss of multiple T-cell antigens, but CD2

and CD4+

– Cytotoxic markers +

– EMA+ as opposed to PCALCL

ALK+ALCL

ALK+ ALCL

EMA ALKALK1

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ALK+ ALCL

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ALK+ ALCL

ALK+ ALCL

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ALK-1

Outcomes in patients with PTCL. (A) Five-year OS rates (Kaplan-Meier

estimates) stratified by PTCL subtype and ALK status only (current WHO

classification).

Martin Bjerregård Pedersen et al. Blood 2017;130:554-557

©2017 by American Society of Hematology

CD30

EBER

Am J Surg Pathol 2019

BRAF V600E

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Angioimmunoblastic T-cell Lymphoma

• Mature T-cell lymphoma with TFH

phenotype– 18% of PTCLs

• Originally described by Frizzera as angioimmunoblastic LAD

• Peripheral LAD, hepatosplenomegaly and B-symptoms

• Anemia, high LDH and hypergammaglobulinemia

• Skin rash in 50% of patients– Macular papular and, less commonly,

purpura, urticaria, nodules, or petechiae. Pruritus was demonstrated in 84% of cases that reported this finding

Balaraman et al. J Am Acad Dermatol 2011

AITL

• LN pathology

– Effacement of normal architecture with prominent neovascularization, follicular dendritic cell proliferation, and hyperplastic, atretic, or absent germinal centers

– Proliferation of immunoblasts

– Background rich in PCs, histiocytesand eosinophils

– B-cell proliferations are common

– IHC: TFH: BCL-6, PD-1, CXCL-13, CD10, ICOS

• Variable loss of CD5 and CD7

• Expansion of CD30+ immunoblasts, that are also EBER positive (B-CELLS, NOT T-CELLS)

• CD21, CD23, CD35 expanded and disrupted FDCs

• DLBCLs or clonal PC proliferations

• Anatomic location: trunk, limbs, head and neck

• Skin pathology– Perivascular infiltrate (47%)

• Nodular/diffuse

• Lymphohistiocytic

– Vascular hyperplasia or proliferation (44%)

– Vasculitis (27%)

– Marginal zone lymphoma-like proliferations

– DLBCL


Botros N et al Am J Dermatopathol 2015

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• RHOA G17V and IDH2 R172K/S mutations in

the skin in 14/18 (78%) and 3/16 (19%) cases

• RHOA G17V mutation was detected both in the

skin and lymph node (LN) biopsies in 7/9 (64%)

cases

Angioimmunoblastic T-cell Lymphoma / MALT-like Presentations


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CD3 CD20

CD3 CD10CD3


KAPPA LAMBDA


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CD3 CD20

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EBER



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CD3 CD20

CD20 CD30


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KAPPA LAMBDA


KAPPA LAMBDA



EBER EBER

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CD3 CD21 CD30

T-lymphoblastic leukemia / lymphoma

• Occasionally patients with ALL

will develop cutaneous

involvement

• The typical presentation is a

solitary firm red to bluish

nodule, often accompanied by

a mediastinal mass.

• Rarely, however, is the

cutaneous manifestation

presenting sign of the patient’s

hematologic malignancy

• Moreover, presentation with a

diffuse exanthem is particularly

uncommon

• Histopathologic findings of

cutaneous involvement of T-

ALL are subtle as bland

malignant blasts may mimic

lymphocytes.

• Diagnostic clues include

substantial crush artifact, an

infiltrate centered on adnexa,

and presence of a grenz zone.

• Immunohistochemical findings

and clinical history are also

vital components in the

diagnosis of this entity.

• IP: CD3+, CD1a+, TdT+,

CD34+, CD99+, CD10+/-,

MPO-


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CD3 TdT

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CD99 TdT

TCR-gamma

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Thank you

for your

attention

!

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10/21/2019...2019/10/03 · 10/21/2019 1 2019 updates on aggressive t-cell lymphomas alejandro a....

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