indolent forms of t-cell lymphomas · indolent forms of t-cell lymphomas philippe gaulard...

Indolent forms of T-cell

lymphomas

Philippe Gaulard

Département de Pathologie & Inserm U955

Hôpital Henri Mondor, Créteil, France

XXVI Congreso National de la Sociedad Espanola de Anatomica Patologica,

Cadiz, may 22-24, 2013

Indolent forms of PTCL

- More questions than answers -

What does « indolent » means?

?

Gisselbrecht et al. Blood, 1998 International T-cell lymphoma project,

J Clin Oncol, 2008

The most common PTCL entities are

aggressive!

• Poor efficacy of conventional therapies in most entities

• Yet, limited improvement in the survival of PTCL patients during the last 20 years

• Limited understanding of the pathogenesis of PTCL…

• Difficult recognition (lack of stringent diagnostic marker)

From “low grade” B-cell lymphomas to specific

entities with adapted therapeutic strategies

The exemple of MALT Lymphoma

Zucca et al. J Clin Oncol 2013

Postulated cell of origin

Translocations Other genetic alterations

Main pathways

T- LGL (NK)

T (more rarely T or NK

STAT3 mut

Apoptosis (Fas-FasL), JAK-STAT

ALCL, ALK+ T (Th2?) t(2;5) or t(2;X) (ALK)

JAK-STAT

ALCL, ALK- (subset)

T (Th2?)

t(6;?) ot t(6;7) (IRF4,DUSP22,..)

AITL T (CD4, TFH) TET2, IDH2, DNMT3 mut +3, +5,….

PDGFR

PTCL,NOS T (CD4>CD8), a subset TFH, rarely T

t(5;9), ITK-SYK, TP63 or other p53-rel genes?

Multiple (del 9p,…)

PDGFRSYK, ….

NK/T, nasal-type

NK (more rarely T or T

del6q21-q25) PRDM1,HACE1, AIM1, .. JAK3 mut

PDGFRJAK-STAT EBV

Hepatosplenic (HSTL)

T (more rarely T

Iso 7q(q10) (?) SYK

Enteropathy-type

T (more rarely T

+9q (9q33) (?), trisomy 1p

PTCLs: genetics is limited !

T- and NK-cell lymphomas

Leukemic/diss. nodal extra-nodal prolymphocytic angioimmunoblastic extranodal NK/T nasal-type

T-LGL leukemia peripheral, nos enteropathy-associated

Indolent NK LPD hepatosplenic ( )

Aggressive NK Leuk ALCL, ALK -

ATL/L (HTLV-1) ALCL, ALK + mycosis

Systemic EBV+ LPD Sezary syndrome

Hydroa vaccineforme-like primary cut. CD30+ LPD

subcutaneous panniculitis-like

primary cut.

primary cut aggressive CD8+

primary cut small/medium CD4+

Updated WHO classification (2008)

« Indolent » forms of PTCL

• Entities that are usually indolent: - T-LGL (NK) - Hydroa vaccifiniforme-like - Cutaneous CD30+ T-LPD - ALCL, ALK negative, adjacent to breast implants (seroma-assoiated) - Primary cut small/medium CD4+ TCL (TFH) - CD8+ T-cell LPD (cutaneous, Gastrointestinal,..?) - NK-cell enteropathy

• Entities that are commonly aggressive, however variably indolent: - any entity (?) - more specifically: ° ATLL (smouldering/chronic forms) ° SPTCL ° PTCL-F/AITL (?) ° ALK+ ALCL limited to the skin (?)

• # early lesions (RCD,…): toward the recognition of a premalignant stage in (some) PTCL entities

Indolent Clonal T(NK)-cell

lymphoproliferative diseases

• Not always early in the sense they do not always transform

• Look morphologically malignant, but have a good behaviour, without therapy

• Best examples: - T-LGL, - Lymphomatoid papulosis - Cut small/medium CD4+ lymphoma - NK-cell enteropathy - Hydroa vacciniforme-like LPD,…

• Clinically, important to recognize

How to distinguish from “clonal expansion of T cells” in benign

situations ?

T- CELL LARGE GRANULAR LYMPHOCYTIC (LGL) LEUKEMIA

• indolent disorder

• Peristent increased number of LGLs (>0.5x109/L, >6 mo) - CD3+, CD8+,TCR +, CD57+, CD16+, CD56- - Clonal TCR gene rearrangement

• adults, frequently asymptomatic

• neutropenia ------> recurrent infections, anemia

• frequent serologic abnormalities (RF++, ANA,..)

• moderate splenomegaly (50%)

T- CELL LARGE GRANULAR LYMPHOCYTE (LGL) LEUKEMIA

• Blood smears (++): « small » lymphocytes with azurophilic granules

• Flow cytometry (+++): incl. KIRs expression for NK,

• Genotype

• Bone marrow smears & histology when LGL count <0.5x109/L - « lymphocytic » infiltration * diffuse interstitial +/- sinuses, small clusters of CD8+/TIA1+/GrB+ cells - + reactive nodules - + “maturation arrest” of myeloid series [spleen: red pulp (cords +/- sinuses), liver: sinusoids] (°) Morice WG et al. Blood 2002;99:268; Costes V et al. Br J Hematol, 2002 Lamy Th & Loughran TP. Blood 2011

• A 68 year-old woman, Pneumonia • Hb 10.9 g/dl, WBC: 2.1 g/dl (neutrophils 19%, lympho : 75% with 45% LGLs) • Mild splenomegaly, no hepatomegaly, no lymphadenopathy • BM biopsy scored as normal

CD57

Gr B CD8

CD20

• By flow and IHC: CD3+, CD5+, CD2+, CD7+ , CD4-/CD8+, CD57+, CD56-, GrB+, TCR +

• Clonal rearragement of genes

Clusters of cytotoxic CD8+, Granzyme B+ CD3+ T cells

E Poullot, P Tas, P Gaulard & T Lamy. In press

CD3

Gr B CD8

Bone marrow biopsy usually not required !

Gr B

CD3

Splenectomy usually not required !

• Disease entity, limited to mature clonal proliferations of « small » LGL, with indolent clinical presentation

• Cell lineage: most often T (CD8+, CD57+), more rarely T ; all with restricted expression of KIRs

• Cases with NK-cell phenotype & genotype referred as “Chronic NK LPD” in the 2008 WHO classification

• Proliferation of activated cytotoxic T lymphocytes (CTLs) of unknown antigen specificity : setting of sustained immune stimulation?

• Alteration of the Fas-Fas ligand pathway (blockade of Fas-dependent apoptosis), which could result in: - autoimmune manifestations - lymphoproliferative syndome

• Constitutive activation of STAT3 resulting from somatic STAT3 mutations in 30-40% of both NK and T forms of the disease

STAT3 mut: a novel biomarker unifying T- and NK- cell LGL Leukemia

Koskela et al. NEJM 2012; Jarez et al. Blood 2012

Teramo et al. Blood 2013; Ragala et al. Blood 2013

Algorithm of the diagnosis of LGL leukemia. Adapted from E Poullot, P Tas, P Gaulard & T Lamy. Oncopathol In press

T : CD 3+, CD 3/TCR+, TCR genes

rearranged

«activated cytotoxic T cells»

NK : CD 3s -, CD 3/TCR -

no rearrangement of TCR

genes

T-LGL

leukemia

Aggressive NK-

cell leukemia

Chronic

NK-LPD-

LGL

leukemia

Both cell subsets mediate «non-MHC» restricted cytotoxicity

EBV, del 6q… ?

LGL

Extranodal NK/T

nasal-type

LGL Leukemia HSTL

CD3

Hydroa vacciniforme-like lymphoma of childhood

Quintanilla-Martinez L, Kimura H, Jaffe ES WHO 2008

• Epidemiology: - Mainly children and adolescents from Asia and Native Americans from Central and South America and Mexico. • Etiology: - mainly neoplastic CD8+T-cells and rarely NK-cells (CD56+) - Some show hypersensitivity to mosquito

bites - defective cytotoxic immune response to EBV-infection as a potential cause • Clinical features: - initially a papulovesicular eruption - subsequently ulceration and scarring - commonly sun-exposed skin - seasonal variation


Courtesy Prof L Quintanilla-Martinez

Morphology: • Neoplastic cells small to medium in size without significant atypia • Infiltration of the Epidermis to the subcutis • Angiocentricity and angioinvasion

Prognosis: - The clinical course is variable,

- recurrent skin lesions up to 10-15 years, - progression to systemic disease can occur

Quintanilla-Martinez L, Kimura H, Jaffe ES WHO 2008



CD3 TIA1 CD8

CD4 CD30 EBER



Cytotoxic (GrB+, perf+), most often CD8+ & CD56-, clonal

Differential diagnosis of Hydroa

vacciniforme-like « lymphoma »

Morphology Phenotype Cytotox EBV T-cell clone

NK/T cell lymphoma, nasal type

Angiocentricity CD3 , CD4-, CD8-, CD56+ CD2+, CD5-, CD7-

+ + -

Primary cutaneous cell lymphoma

Epidermotropism and/or

Panniculitis

TCR , CD3+, CD4-, CD8- CD56 +/-

CD2+, CD5-, CD7+/-

- - +

Primary cutaneous CD8+ Agressive

epidermotropic T-cell lymphoma

Epidermotropism Folliculotropism

TCR , CD3+, CD4-, CD8+, CD56-

+ - +

Primary cutaneous CD4+ small medium

T-cell lymphoma

Pleomorphous TCR +, CD3+, CD4+, CD8-, CD56-

+ - +

Hydroa vacciniforme-like

lymphoma

Small/medium with mild atypia Children++

Most often CD8+, CD56+, TCR +,

+ + +

Blastic plasmacytoid dendritic cell

neoplasm

Monomorphous TCR-, CD3-, CD4+, CD8-, CD56+

CD123+, BDCA2+…

- - -

• Iry cutaneous or secondary (°))?

• If primary cutaneous,

- LP or Iry cutaneous ALCL

- favourable outcome

• If secondary,

- ALCL, ALK-positive

- ALCL, ALK-negative

- PTCL, NOS (CD30+)

(°) Differential diagnosis with any other T-cell lymphoma entity which can show CD30

expression (incl. transformed/tumor stage MF, nasal-type NK/T, etc…)

CD30

CD30+ T-cell LPD in the skin

Importance ++++ of

the clinical

context/staging

• Staining for ALK,…

• Regional LN involvement by Iry cut ALCL does not

impact outcome (~~90% 5 y OS) CD30

CD30+ T-cell LPD in the skin :

Iry cutaneous or secondary?

Case A Dogan, EAHP, Uppsala, 2010

ANAPLASTIC LARGE LYMPHOMA, ALK- and breast

implants (« seroma-associated primary ALK-negative

ALCL adjacent to breast implants »)

Kim B et al. Plast Reconstr Surg 2011

CD30 TIA1

• A 61 year-old woman, injured with knifes in 1970, several breast implants since 1980 • 01/2012, large mass + seroma (adjacent to the implant) : biopsies

CD30

PAX5

CD8

GrB

CD30+, CD15-, EMA+/- , ALK1- CD20-, CD79a-, PAX5-, CD3-, CD2+, CD5-, CD7-, CD4-, CD8+, TIA1+, GrB+, CD56-, EBV - T-cell clone (PCR )

• « seroma-associated » primary ALK-negative ALCL adjacent to breast implants - atypical presentation with a tumour mass - morphology « Hodgkin-like »

• treatment : 6x CHOP (large mass, 8x12 cm)

• Persistent CR since june 2012

BCA-1=CXCL13

CXCR5 CXCL13 BCL-6 Il6R IL21 CD84 CD40L CD200/OX2 ICOS PD1

TFH

AITL (de Leval et al. Blood 2007)

PTCL-F (Huang et al. AJSP 2009)

Iry cut CD4+ small /medium

pleomorphic

T-cell lymphoma (Rodriguez Pinilla et al. AJSP 2009)

T-cell lymphomas expressing TFH markers ?

Primary cutaneous CD4+ small/medium-sized pleomorphic

T-cell lymphoma

Primary cutaneous CD4+ small/medium sized pleomorphic T-cell

lymphoma

CXCL13 PD1

Rodriguez Pinilla SM, et al. Am J Surg Pathol. 2009;33(1):81-90

Provisional entity of the 2008 WHO classification, most likely identical to cutaneous

« Pseudo-T cell lymphomas » described previously (Cetinozman F et al. Am J Surg Pathol 2012;36)

Diagnostic usefulness of TFH markers in skin

biopsies (PD1, CXCL13,..)

• AITL : common expression (PD1, CXCL13)

• Iry cutaneous CD4+ small/medium-sized PTCL :

common expression (PD1, CXCL13)

• Mycosis fungoides : occasional expression of

PD1, more rarely CXCL13

• Sézary cells

– Common expression of PD1 in both blood and skin Cetinözman F, et al. Am J Surg Pathol 2011

– CXCL13? Picchio MC, et al. Cancer Res 2008;68:7137–46

Indolent CD8+ cutaneous T-cell

lymphoproliferation (ear-type)

Patient 3: nodules of both ears

Petrella T et al. Am J Surg Pathol 2007; 31 Beltraminelli et al., JCP, 2009; Li et al., Histopathology, 2009; Suchak et al., JCP, 2009

Géraud et al., BJD, 201; Swick at al., JCP, 2011; Zeng et al, JCP, 2012

Coutesy, T Petrella

CD3

CD8

TIA1 MIB1

• median age, around 60 y), male predominance

• Slowly growing lesion for several months or years, most often unique – Ear: 70%

– Nose: 20%

– Other: 10% (foot and thigh)

• Spontaneous regression possible

• Characteristic histological and phenotypic features - small/medium, slightly pleomorphic - CD3+, CD2+, usually CD5-, CD7-, CD8+, TIA1+, GrB-, CD56-, bF1+, - EBV-

• Clonal

• No spreading (Staging negative)

• Treatment : (surgical excision), radiotherapy

• Local relapse possible (1 contro-lateral relapse)

• All patients in CR or with a stable lesion (follow-up of more than 16 years for the oldest case)

21 patients (FSGCL and EORTC CL groups) Indolent CD8+ cutaneous T-cell

lymphoproliferation (ear-type)

21 Pts from the FSGCL & EORTC, T Petrella et al, unpublished

Yet, this lesion doesn’t fit into any category of the WHO

nor EORTC classifications

• Is it a real low grade lymphoma or pseudolymphoma? - histologically it looks like a lymphoma (atypical cells,

clonality, loss of antigens, relapses)

- clinically it is not a lymphoma (localized disease, good

outcome

• Why this ear tropism (+ nose)? - Is there a local trigger agent (infectious, chemical, physical) ?

• Genetic abnormalities?

• How to designate this lesion? - This lesion must not be confused with more aggressive

lymphomas

Yet, the term “Indolent CD8+ cutaneous lymphoid proliferation (ear-

type)” seems to be appropriate?

Indolent CD8+ cutaneous T-cell

lymphoproliferation (ear-type) - more questions than answers -

• 7 patients - histologically it is a lymphoma (atypical cells, clonality, loss of

antigens, relapses)

- clinically it is not a lymphoma (localized disease, good

outcome

• Why this ear tropism (+ nose)? - Is there a local trigger agent (infectious, chemical, physical) ?

• Genetic abnormalities?

• How to designate this lesion? - This lesion must not be confused with more aggressive

lymphomas

Similar Indolent CD8+ T-cell

lymphoproliferation may occur in the GI tract (Dr Perry et al. EAHP Lisbonne 2012, Abstract LYS017)

ileon

colon

• A 31 year-old man, presenting without chonic diarrhea, without B symptoms • Multiple polypoid lesions (ileon, colon) at endocopy • Clinical staging & laboratory tests: normal

CD3 CD20

CD8 TiA1

• Immunophenotype : CD20-, CD2+, CD3+, CD5+, CD7+, CD4-, CD8+, CD56-,

CD30-, TiA1+, GrB-, proliferative index <10% (Ki67), EBERs negative

• T cell clone.

PTCL, NOS????

Or…

Conclusion

• This patient was given polychemotherpy for PTCL,NOS

(CHOP, DHAOX) without CR; therapay was stopped a year

ago: patient well but with persistent non evolutive lesions

(same pathological features)

• 6 others similar cases reported by Dr Perry

• Unknown physiopathology: continuous stimulation by

an unknown antigen inducing a clonal T-cell response ???

• Similarities with:

- NK-cell enteropathy: a benign NK-cell lymphoproliferative

disease mimicking intestinal lymphoma (Mansoor et al,

Blood 2011)

- Cutaneous indolent CD8+ lymphoproliferation of the ears

(Petrella et al, AmJSurgPath 2007)

How should we call this indolent clonal T-cell

lymphoproliferative disease?

Indolent CD8+ T-cell lymphoproliferative disorder of

the GI tract (Dr Perry et al. EAHP Lisbonne 2012, Abstract LYS017)

CD3 CD56

8 patients, 27-68 yo

Asymptomatic or variable

abdominal symtoms

Single or multiple GI sites

Endoscopy: superficial +/-

ulcerated lesions

No enteropathy

CD3+, CD5-, CD4-/CD8-,

CD56+, GrB+, EBV-, TCR

polyclonal

Alive WD 22 to 120 months

after diagnosis (5/8 untreated)

Mansoor et al. Blood 2011

NK-cell enteropathy

« Indolent » forms of PTCL

• Entities that are usually indolent: - T-LGL (NK) - Hydroa vaccifiniforme-like - Cutaneous CD30+ T-LPD - ALCL, ALK negatif adjacent to breast implants (seroma) - Primary cut small/medium CD4+ TCL (TFH) - CD8+ T-cell LPD (cutaneous, Gastrointestinal,..?) - NK-cell enteropathy

• Entities that are commonly aggressive, however variably indolent: - any entity (?) - more specifically: ° ATLL (smouldering/chronic forms) ° SPTCL ° PTCL-F/AITL (?) ° ALK+ ALCL limited to the skin (?)

• # early lesions (RCD,…): toward the recognition of a premalignant stage in (some) PTCL entities

Adult T-cell leukaemia/lymphoma

(HTLV1+) (ATLL)

• A peripheral T-cell neoplasm caused by HTLV1

• Endemic : South Japan, Caribbean islands, Central Africa

• Adults (long latency > 20y)

• Morphology highly variable: pleomorphic small, medium or large; convoluted nuclei (« flower » cells)

• Phenotype: CD3+, CD4+, CD7-, CD25+, FoxP3+

• Genotype: clonal integration of the viral HTLV1 genome

• Clinical variants with critical prognostic relevance: - smoldering (skin) - chronic - lymphomatous - acute (leukemic)

Serological tests for HTLV1 to be performed in any case of PTCL

Frequency Skin involvement

Non-cutaneous

sites

Lymphocytosis

5 year OS

Acute 65% Common (50%)

Spleen, liver,LN,…

Yes 5%

Lymphoma 30% Common Adenopathies,.. No 5%

Chronic <5% Common Adenopathies Liver, lung,…

Rare 27%

Smoldering <5% Constant …. No 62%

Leucémie/lymphome T de l’adulte (HTLV-1) Adult T-cell leukaemia/lymphoma (HTLV1+)

(ATLL)

•Overall, the skin is the most common extralymphatic site of involvement (>50%)

•Diagnostic importance of skin biopsy specially in chronic & smoldering variants

Leucémie/lymphome T de l’adulte (HTLV-1)

Forme indolente…

CD25 (IL2®)

Adult T-cell leukaemia/lymphoma (HTLV1+) (ATLL)

Pathological features

ALK-postive ALCL limited to the skin:

some cases with indolent outcome, at

least in children?

Oschlies et al. Haematologica 2013

« In these 6 pediatric cases of ALK+ ALCL, therapy confined to local measures

was sufficient to induce cure. »

Angioimmunoblastic

T-cell lymphoma

AITL

PTCL-F

TFH

Subset of CD4+

cutaneous T-cell

lymphomas

Follicular variant of PTCL,NOS : a subgroup with variable outcome, most likely related to AITL?

PTCL, NOS

With TFH

phenotype

(« TFH-like »)

Is the group of so-called « follicular PTCL » an “early”

TFH-derived PTCL and is it related to AITL?

De Leval et al. AJSP, 2002

M Qubaja et al. Hum Pathol 2008

CM Bacon et al. Br J Haematol 2008

Y-L Huang et al. AJSP, 2009

PD1 PD1

Follicular variant of PTCL, NOS ?

• Nodular growth pattern

– may mimick follicular

lymphoma

– small/medium sized T cells

• CD4+ Bcl6+ CD10 +/-,

• Expression of TFH markers

(CXCL13+, PD1+, ICOS+)

• t(5;9) translocation (SYK-ITK

fusion) in a subset of cases

• Relationship to AITL?

de Leval L et al. AJSP 2001; Streubel B et al. Leukemia 2006; Bacon C et al. Br J

Haematol 2008; Qubaja M et al. Human Pathol 2008; Huang L et al. AJSP 2009

CD3

Pt 23: t(5;9) positive

PTCL,NOS with follicular pattern (follicular

variant)

1998:

• 62 y old man

• B symptoms

• Cervical ADP

• Skin rash

• Hyper glob, Coombs test+

1998

2006

2007

The spectrum of AITL might be wider than expected

PD1

PD1

PD1

M Qubaja et al. Hum Pathol 2008

Y-L Huang et al. AJSP, 2009

Clonality # Malignancy

Some (rare) «PTCL» entities

with indolent behaviour

- terminology?

- need to be recognized

- mostly extranodal

(cutaneous or mucosa)

Cytotoxic (CD8+/NK) T-cell

LPD in the skin or GI tract: a

novel subgroup/entity?

Uncover the oncogenic

pathways

Disease subgroups in other

entities ?

Recognition needed !

ILSG, 1996

R Delarue et al. Blood 2013 Kluin-Nelemans et al. NEJM 2012

The exemple

of MCL

R-CHOP/R-DHAP + ASCT

• In addition, indolent forms of MCL are recognized !

indolent forms of t-cell lymphomas · indolent forms of t-cell lymphomas philippe gaulard...

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