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The dark side of innate and adaptive immunity - cytotoxic and dendritic cell lymphomas 2005 Dominic Spagnolo PathCentreWA Dr Vincent McGovern 1915-1983.

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Presentation on theme: "The dark side of innate and adaptive immunity - cytotoxic and dendritic cell lymphomas 2005 Dominic Spagnolo PathCentreWA Dr Vincent McGovern 1915-1983."— Presentation transcript:

1 The dark side of innate and adaptive immunity - cytotoxic and dendritic cell lymphomas 2005 Dominic Spagnolo PathCentreWA Dr Vincent McGovern 1915-1983 …attack of the clones

2 The players r Components of the innate and adaptive arms of the immune system –extreme form of immune dysregulation  CD8+ (  +) T cells   + T-cells 3 NK cells 3 NK-associated T-cells 3 Dendritic cell (type 2) precursor

3 Why?? r Follicular lymphomas are boring r Very different from B-cell lymphomas –least common of the uncommon (<2%) –diagnostically problematic (mimic other NHL) phenotypic promiscuity diagnostic armamentarium –clinically distinctive extranodal, limited stage –tissue restricted lymphocyte subsets aggressive, chemoresistant hemophagocytic syndrome chronic antigenic stimulation, impaired immunity

4 Agenda 1. Review clinicopathological features –WHO 2001 –WHO-EORTC (2005) classification for cutaneous lymphomas 2. Normal lymphocyte immunobiology 3. New data 4. CD4+ CD56+ hematodermic neoplasm

5 MARROW STEM Myeloid progenitor Common lymphoid progenitor B cell L2 L3 Mature DC immature DC NK CD8+ CD4+  T cell 90-95%  T cell 5-10%

6 ADAPTIVE immunity  + T CELLS - CD8+ - CD4+ B cells, plasma cells INNATE-LIKE “Bridge” innate and adaptive  + T CELLS NKT CELLS T reg cells B-1 B cells - Specific tissue distributions - - Site-specific homing mechanisms - Blood 1 0 2 0 lymphoid tissues Tissue-restricted INNATE immunity DENDRITIC CELLS NK CELLS Macrophages, pmn, mast cells

7 Natural killer lymphocytes NK and NK/T lymphomas

8 Immunoregulatory cytokines chemokines (adaptive immunity) Natural cytotoxicity non-MHC cytotoxicity (innate immunity) NK CELL CD56 NCR CLR KIR costimulatory perf TIA-1 granz TCR - G CD3  Phenotypicpromiscuity!

9 NEJM 2000; 343:37-49 Natural killer receptors (NKRs)

10 r HLA-recognising receptors –Killer Ig-like receptors (KIR) –C-type lectin-like receptors (CLR) CD94/NKG2 family heterodimers activating or inhibitory Most NK receptors are not specific for NK cells NK receptors activating  Non-HLA binding – NKG2D homodimer – Natural cytotoxicity receptors (NCR) NK-specific: 2 NCRs only (NKp46; NKp30) – Costimulatory receptors e.g. 2B4; NTBA (activ/inhib)

11 Diagnostic utility of NKR expression r Abnormal patterns of NKR expression –restricted repertoires (KIR) indicative of pathological state, not necessarily lymphoma receptor genes do not rearrange –transcripts may be of prognostic relevance –normal reference ranges to be established correlation with other clonality studies

12 WHO Aggressive NK cell leukemia Chronic NK-lymphocytosis E/nodal NK/T- cell lymphoma, nasal type NK cell proliferations

13 E/nodal NK/T-cell lymphoma, nasal type r Asia, C & S America; American Indians –rare in West r Upper respiratory tract - nasal, n/pharynx –rhinitis, bleeding, mass –bone destruction - high frequency maxilla, orbit, palate r Skin, subcutis, GIT, lung, testis, female genit. –skin second most common site r Extranasal cases - more often advanced stage

14 Extranodal NK/T lymphomas r Morphology heterogeneous, clinically irrelevant –Necrosis, apoptosis death receptor activation: Fas-FasL, TRAIL --> --> caspase cascade --> apoptosis cytotoxic granule exocytosis –angio-invasion, angio- destruction chemokines Mig and IP-10 endotheliotoxic (CXC family) r Activated cytotoxic phenotype –Perforin+, Granzyme+ (cf. TIA-1+ only) r EBER+ (site-, geography-dependent)

15 Extranodal NK/T-cell lymphoma, nasal type r NKR expression –CD94/NKG2A+ majority CD94 mRNA +ve ?? better prognosis than -ve –KIR+ minority of cases; restricted repertoire r Cutaneous lymphocyte antigen+ (>50%) –cutaneous cases particularly –poor prognostic factor r Del (6q); gains at 1p32-pter –multiple recurrent gains/losses

16 r Aggressive, even stage 1E –early systemic spread, typically extranodal skin, subcutis, GIT, testis, soft tissue; marrow leukemic (aggressive NK cell leukemia) –chemoresistance - MDR-1 (P-glycoprotein) –hemophagocytic syndrome ~10% (TNF  ; NF  B) r 5 yr OS and DFS <40%; DXT mainstay of Rx –IPI of prognostic significance –no effect - age, stage, p53, cell size, EBER, Rx, lineage (Ng SB et al; Mod Pathol 2004) E/nodal NK/T-cell lymphoma, nasal type

17 BLOOD 1997; 89:4501-4513 CD56 POSITIVITY Male predominance Advanced stage, aggressive EXTRANODAL - liver, spleen, intestine, lung, URT Little or no peripheral adenopathy Immunosuppressed BLOOD 1996; 87:1474-1483

18 Aggressive NK-cell leukemia r Japan, Asia >>> West (RARE!) –largest series 22 cases (Suzuki R, Leukemia 2004) r Relatively young, fever, B symptoms, anemia r Leukemic presentation –minority lymphoma-like adenopathy, little or no blood involvement r Hepatosplenomegaly; coagulopathy –frequent GIT, skin, nodes; marrow subtle or overt –large granular lymphocytosis r Aggressive - death in months; HPS frequent

19 Aggressive NK-cell leukemia r sCD3-, cCD3+, CD4-8-, CD56+ r TCR germline r EBER+ r SKY and CGH studies –frequent 6q, 13q, 11q, 17p13 deletions (similar to NK/T lymphoma, nasal type) –translocations involving Xp21-pter; 8p23 Message: –Don’t undercall as an indolent large granular lymphocytosis / leukemia

20 The mucosal immune system CD3 EnteropathytypeT-celllymphoma

21 Enteropathy-type T-cell lymphoma (ETTL) r Arises from phenotypically heterogeneous subsets of IELs –cytotoxic T lymphocytes –natural killer cells (rare) r Coeliac disease - clinical or latent –HLA DQA1*0501; DQB*0201; DRB*0304 –adults, recent onset –refractory sprue –ulcerative jejunitis

22 T 3 thoracic duct 4 mesent LN CCL 25 CCR9 5  E  7 [CD103; HML-1] E- Cad 5 2 Peyer’s patch MAdCAM-1 L-selectin  4  7 integrin Mucosal lymphocyte trafficking Ag 1 EPI M IEL lamina propria 6

23 TCR  CD3 CD8  CD103 15% TCR  CD3 CD8  CD56 15% EPI M IEL TCR  CD3 CD8 CD103 70% NORMAL REFRACTORY SPRUE / UJ RARE MAJORITY TCR- (or  +) sCD3-, cCD3+ CD4-, CD8 - CD103+ UNCOMMON ETTL MAJORITY ‘Type A’ TCR  CD103 3- 8- cCD3+ (8+) MINORITY ‘Type B’ TCR  3- CD8  CD56 cCD3+ COELIAC MAJORITY RAREUP TO 30% CLONAL TCR  -R “Cryptic ETTL”

24 Enteropathy-type T-cell lymphoma r Localised disease typically –may disseminate LN, liver, spleen, lung, skin r Mass may be absent –ulcers, obstruct, perforate, bleed r Enteropathic mucosa ~50% –proximal >> distal; affected by gluten free diet r Aggressive course - death in months r Not all intestinal T-NHL are ETTL !!

25 Enteropathy-type T-cell lymphoma r CGH and microsatellite studies – >85% recurrent gains/losses at several loci –gains at 9q33-34 ~60%, both types A and B C-ABL and NOTCH-1 – >3 imbalances prognostically unfavorable –LOH at 9p21 one third cases (type A >> B) site of suppressors p14/ARF, p15/INK4b, p16/INK4a

26 Cutaneous cytotoxic T-cell lymphoma (non-ALCL) r Similar homing mechanisms as in intestine r Skin-homing T cells express: –CLA: binds to E-selectin on cutaneous vascular endothelium –CCR4: binds to CCL17(TARC) expressed on cutaneous vascular endothelium –CCR10: ligates CCL27 on keratinocytes

27 Aggressive epidermotropic CD8+ CTCL Prof. L Cerroni Provisional entity WHO/EORTC 2005 Localised or disseminated Patches, plaques, papulonodules, tumours Ulceration Adnexotropism, fat rimming Extranodal spread - lung, testis, CNS, oral Median survival 32 mos 0% 5 yr survival

28 Gamma-delta (  ) T-cells  + T-cell lymphomas

29   T cells r “Innate-like” lymphocytes –bridge innate and adaptive immune systems rapid cytokine producers; cytotoxicity –important roles in infection immune regulation immune surveillance r Restricted tissue distribution –5 - 15% of peripheral blood lymphocytes –10 - 15% splenic red pulp –thymus, nodes, GIT, other mucosae, liver, skin

30   T cells r Lack recirculation r Receptors of very limited diversity (Ig-like) r No MHC restriction or Ag processing r No clonal expansion r Not a homogeneous population –most CD4-8-; IELs are CD8  + –subclassification according to V segment usage V  1 - naïve/fetal T-cell phenotype (CD45RO-) - spleen, thymus, germinal centres of nodes V  2 - memory/adult phenotype (CD45RO+) - blood, interfollicular nodes & tonsils, skin

31   T-cell lymphomas r Sites –hepatosplenic (immature V  1+) - WHO 2001 –mucocutaneous and epithelial sites (mature V  2) r Limited stage, but aggressive –necrosis, apoptosis –hemophagocytic syndrome r Mimic and overlap other cytotoxic lymphomas –SPTCL, NK/T nasal type, ETTL

32 Hepatosplenic T-cell lymphoma  Most from naïve splenic  T-cells (V  1+) r Young adult males –hepatosplenomegaly –thrombocytopenia, anemia, leukopenia (~45%) –no adenopathy; other sites rare –leukemic presentation rare   + cases occur (females; wider age range) r Chronic Ag stimulation + altered immune state –post-organ transplant, SLE, HD, chronic Hep B

33 Hepatosplenic T-cell lymphoma r Marrow+, but may be subtle, sinusoidal r Lymphocytosis minor or absent at Dx –blastic change +/- leukemic terminally r Aggressive course - poor chemosensitivity –median survival 16 months –indolent, relapsing prodrome in some r Must exclude mimics –T-LGL –aggressive NK leukemia –others

34 Blood 1998; 91: 1723 - 1731 Arnulf, B et al Skin/subcutis GIT, lung, URT Testis, breast, thyroid Primary nodal - uncommon Lymphoblastic 50% T-cell LGLL - uncommon Clinicopathologically similar to other cytotoxic lymphomas at the same sites Activated cytotoxic phenotype cf. hepatosplenic

35 p Extremities, trunk p Mucosal, extranodal - nodes, spleen, marrow uncommon p HPS in SPTCL-like cases p Chemoresistant - 15 mos median survival  Mature, cytotoxic, V  2+ CD4-, CD8- (few CD8+) CD56+/-; EBER-  phenotype: independent predictor of decreased survival BLOOD 2003; 101:3407-341233 cases

36 Subcutaneous panniculitis-like T-cell lymphoma (WHO-EORTC 2005)

37 p Mainly young adults, indurated s/cutaneous nodules/plaques, extremities > trunk > face - extracutaneous spread rare Subcutaneous panniculitis-like T-cell lymphoma r Systemic symptoms frequent; –haemophagocytic syndrome up to 50% r Aggressive typically –median survival 27 mos (Go & Wester, review 2004) –high dose chemo/stem cell Tx effective in some –some indolent, remitting/relapsing with chemoRx, related to phenotype –rarely may disseminate to nodes, e/nodal sites

38 Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) Pre- 2005 view 2 forms of SPTCL   + SPTCL (75%)   + SPTCL (25%)

39 BLOOD 2005; 105:3768-3785 3 WHO-EORTC 2005 ‘SPTCL’ limited to this type 3 CD8+, CD56- 3 limited to subcutis 3 indolent  + SPTCL   WHO-EORTC 2005 classified as  + CTCL (provisional entity) 3 CD4-, CD8-, CD56+ 3 +/- dermal / epidermal 3 aggressive  + SPTCL 

40 a neoplasm of plasmacytoid dendritic cell precursors DC2 Plasmacytoid dendritic cell (pDC) precursor plasmacytoid monocytes CD4+ CD56+ hematodermic neoplasm (Blastic NK-cell lymphoma) WHO-EORTC 2005

41 CD34+ progenitor Myeloid progenitor Monocyte IL4 GMCSF CD14+ CD11c+ DC1 IFN  TH2TH2 TLR 7,9 signalling TH1TH1 IL12 T CELL ACTIVATION TLR 2,3-6,8 signalling Lymphoid progenitor Plasmacytoid DC IL3 CD40L(CD154) DC2 CD123+ CD14- CD11c-

42 J Exp Med 1997; 185:1101-1111 Nature Med 1999; 5:919-923

43 Am J Surg Pathol 1999; 23(2):137-146 Am J Surg Pathol 1997; 21(10):1223-1230

44 CD4+ CD56+ hematodermic neoplasm (Blastic NK-cell lymphoma) - WHO/EORTC marrow (80%) LN (>50%) spleen/liver (20%) p >60% stage IV at Dx BLOOD 2002 Feuillard J p Rare, aggressive p Cutaneous +/- leukemic p M>F, median 60s p Violaceous skin plaques, nodules, non-ulcerating

45 CD4+ CD56+ hematodermic neoplasm (Blastic NK-cell lymphoma) - WHO/EORTC r Leukemic - often at Dx, or develops rapidly r Poor prognosis - median survival 13 mos r Indolent course in some ?predictable –possible favorable factors skin-confined; age <40; TdT+ Rx with leukemia-type regimes induction of remission + allogeneic SCT

46 r Lineage negative (T-, B-, Myeloid, NK-) r CD45RA+; Granz B; TdT -/+ r Antigen receptor genes germline r Cutaneous lymphocyte antigen +ve r BDCA-2, BDCA-4 positive (novel markers) r del(5q) CD4+ CD56+ hematodermic neoplasm (Blastic NK-cell lymphoma)

47 r Association with MDS or MPD (15-20%) –AMML evolution in small subset r Acquisition of some myeloid markers during disease progression, e.g. CD33 r ?? Relation to myelo-monocytic lineage –plasticity; common ancestry pDC, Myeloid, NK

48 Malignant lymphoma of plasmacytoid T-cells Morphologic and immunologic studies characterising a special type of T-cell Hans Konrad Muller-Hermelink et al Am J Surg Pathol 1983; 7(8):849-862 (Myelomonocytic leukemia 3 mos after Dx)

49 Am J Surg Pathol 2004; 28:585-595 CMML - 4 Unclass. chronic MPD - 1 AML - 1 MPD/MDS - 1 AMoL - 2 p pDC accumulations in Nodes, Marrow, Skin p Clonal identity 1 case by FISH AML and pDC cells both with monosomy 7 p Most CD56 negative

50 ACKNOWLEDGEMENTS King Edward Memorial Hospital Fremantle Hospital Princess Margaret Hospital Western Diagnostic Pathology St. John of God Pathology Royal Perth Hospital PathCentre Michael Platten, Lorella Manso Jeremy Taylor, Suzanne Cairns

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