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Diagnostika lymfomů Extranodální lymfomy Doc. MUDr. L. Boudová, Ph. D.

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Prezentace na téma: "Diagnostika lymfomů Extranodální lymfomy Doc. MUDr. L. Boudová, Ph. D."— Transkript prezentace:

1 Diagnostika lymfomů Extranodální lymfomy Doc. MUDr. L. Boudová, Ph. D.

2 Contents WHO Classification 2008

3 Lymphomas Clonal disorders of lymphoid cells at various stages of differentiation HODGKIN L. NON-HODGKIN L.  immature cells (precursors)  mature cells  B  T Note: Hodgkin lymphoma is also a (mature)B-cell lymphoma. Distinction clinical histological

4 Lymphoid malignancies Epidemiology 90%: B; FL+ DLBCL – 60% 4% of all new cancers each year Incidence increasing per 100 000: 34 lymphoid neoplasms

5 Lymphoma diagnosis Sample Lymph node Bone marrow Spleen, extranodal tissue Cerebrospinal fluid

6 Lymphoma diagnosis  Histology, cytology  Immunohistochemistry Ag detected in tissue slides  Molecular biology Clonality, lineage – gene rearrangements Translocation detection, mutations  Flow cytometry  Clinicopathological correlation, esp. T-cell lymphomas difficult to diagnose

7 Gene rearrangement (PCR, Southern blot) Clonality and lineage  B-cells: IgH  T-cells: T-cell antigen receptor Characteristic translocations Mantle cell lymphoma t(11;14) Follicular lymphoma, diffuse large B-cell l. t(14;18) Anaplastic large cell lymphoma t(2;5) Burkitt lymphoma t(8;14) Lymphoma diagnosis molecular biology

8 B-cell lymphoma Clonal disorders of B-cells at various stages of differentiation of immature cells - lymphoblasts B-acute lymphoblastic leukaemia - frequent, children B-lymphoblastic lymphoma - rare of mature B-cells most common: diffuse large B-cell lymphoma, follicular; plasma cell myeloma

9 Mature B-cell lymphomas Chronic lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Hairy cell leukemia Plasma cell myeloma Monoclonal gammopathy of unknown significance Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma= MALT Nodal marginal zone B-cell lymphoma Splenic marginal zone lymphoma

10 Mature B-cell lymphomas Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Burkitt lymphoma/leukaemia

11 T-cell lymphoma Precursor T-cell lymphomas -T-acute lymphoblastic leukaemia -T-lymphoblastic lymphoma –Mature T-and NK cell neoplasms uncommon –10% of all NHL Most frequent : peripheral T-cell lymphoma, unspecified large cell anaplastic lymphoma  often difficult to diagnose

12 Most common T-cell lymphomas 1. Leukaemic/disseminated adult T-cell leukaemia - HTLV 1 2. cutaneous - mycosis fungoides, Sezary syndrome, primary cut. anaplast. lymphoma 3. other extranodal - extranod. NK/T - nasal, enteropathy assoc. 4. nodal - peripheral T-cell lymphoma, NOS, anaplastic large cell lymphoma

13 NK/T-cell lymphoma of nasal type EBV, angiocentric, destructive South America, Asia Lethal midline granuloma NK/T-cell l. Wegener granulomatosis Cocaine abuse


15 Diffuse large B-cell lymphoma

16 aggresive, potentially curable COMMON! 1/3 of all lymphomas of adults (med. 64 ys) nodal OR extranodal (1/3) GIT, skin, CNS, testis bone, soft tissue, salivary glands, Waldeyer ring, lung, kidney, liver, spleen, female genital tract

17 Diffuse large B-cell lymphoma Primary OR secondary Chronic lymphocytic leukemia Follicular lymphoma Marginal zone B-cell lymphoma Nodular lymphocyte predom. Hodgkin l. Risk factor: immunodeficiency (often EBV+)

18 Diffuse large B-cell lymphoma Morphologic variants Centroblastic Immunoblastic Plasmablastic DLBCL subtypes T-cell/histiocyte rich CNS Skin- leg type EBV positive - elderly

19 Special lymphomas of large B-cells Mediastinal (thymic) Intravascular Chronic inflammation Lymphomatoid granulomatosis ALK positive plasmablastic Arising in HHV8 Castleman dis. Primary effusion

20 Diffuse large B-cell lymphoma, Giemsa

21 Diffuse large B-cell lymphoma Differential diagnosis Tumors Haematological: lymphomas – peripheral - B, T precursors - B, T myeloid neoplasm Non-haematological: carcinoma, sarcoma, GIST, melanoma, seminoma, glial tumors Reactive disorders: infectious mononucleosis, Kikuchi

22 T-cell /histiocyte rich B-cell lymphoma diffuse large B-cell lymphoma neoplastic B-cells scarce majority reactive T-cells, histiocytes Small B-cells rare BUT areas with increased numbers of small B-cells  associated NLPHL ? CD20 Diffuse/ vaguely nodular

23 T-cell /histiocyte rich B-cell lymphoma Differential diagnosis 1. Hodgkin lymphoma - classical - NLPHL (nodular paragranuloma) 2. T-cell lymphoma 3. Reactive disorders – T/HRBCL interfollicular

24 Diffuse large B-cell lymphoma clinicopathological subtypes mediastinal

25 Mediastinal DLBCL Thymus Female, 30 ys Anterior mediastinal mass Superior vena cava syndrome Clinicopathological differential diagnosis?


27 Mediastinal DLBCL Compartmentalising fibrosis Polymorphic large cells, abundant pale cytoplasm CD20, CD23, CD30, CD45

28 Mediastinal DLBCL – differential diagnosis Problems 1. small biopsies, crushed cells, small areas for IH 2. background: small ly, eosinophils; RS cells 3. clinicopathological features – med. mass, young woman Traverse-Glehen : Mediastinal Gray Zone Lymphoma. The Missing Link Between Classic Hodgkin Lymphoma And Mediastinal Large B-Cell Lymphoma. Am J Surg Pathol, Nov. 2005, 29, 1411-1421 GRAY ZONE

29 Classical Hodgkin lymphoma Nodular sclerosis

30 Borderline cases


32 BCLUWFIBDLBCLACHL DLBCL vs. CHL morphology, IHC Garcia, Histopathology 2005

33 BCLUWFIBDLBCLACHL DLBCL vs. CHL morphology, IHC Traverse-Glehen AJSP 2005

34 DLBCL Differential diagnosis versus Burkitt lymphoma

35 1. endemic (Africa) 2. sporadic (young, rare) 3. immune deficiency-associated - HIV! t(8;14) starry sky


37 BCLUWFIBDLBCLABL DLBCL versus Burkitt morphology, IHC, genetics Chuang AJCP


39 Extranodal lymphomas the primary tumor is extranodal (not nodal) The biggest mass is extranodal at the time of the diagnosis Diagnosis may be nmore difficult than in the LN – other tumours may be more common in extranodal localizations (carcinomas..) – think of the possibility of a lymphoma Most common: GIT, skin, Waldeyer,CNS, testis, bone soft tissue, salivary glands, lung, kidney, liver, spleen, female genital tract Histological types: DLBCL, MALT l.

40 Gastrointestinal lymphomas most common extranodal lymphomas 50%

41 Klinické symptomy často necharakteristické! pokročilé: tumor v břiše, srůsty kliček, perforace lymfadenopatie hepatosplenomegalie KO: lymfocytóza,  LDH endoskopický nález

42 GI lymphomas Type  B DLBCL, MALT MCL, FL  T EATL Site  Stomach  Intestines (ileocaec., jejunum, duodenum)

43 Diffuse large B-cell lymphoma of the stomach


45 MALT lymphoma versus DLBCL Gastric DLBCL  de novo  transformation of a low-grade lymphoma clonal progression in time  Independent coexistence of 2 clones: low /high grade component DO NOT USE “HIGH-GRADE MALT LYMPHOMA“

46 MALT lymphoma  stomach, intestine (IPSID) chronic antigenic stimulation - Helicobacter pylori Regulation: specific activated T-cells Slow progression- 90%: stage IE, IIE (bone marrow involvement: rare, 10%)

47 Helicobacter pylori Chronic gastritis

48 Diseases associated with Helicobacter pylori infection Chronic gastritis Peptic ulcer Gastric carcinoma Gastric MALT lymphoma DiseaseAssociation Chronic gastritisStrong causal association Peptic ulcer diseaseStrong causal association Gastric carcinomaStrong causal association Gastric MALT lymphoma* Definitive etiologic role

49 MALT lymphoma of the stomach

50 MALT lymphoma Different sites common features  Architecture  Cytology  Immunophenotype extrafolik. infiltráty folikulární kolonizace lymfoepiteliální léze monocytoidní, plazmat. buňky

51 Macroscopy: often noncharacteristic Microscopy: Wotherspoon criteria - spectrum 0 normal mucosa 1chronic active gastritis 2chronic active gastritis with lymphoid follicles 3suspicious lymphoid infiltrate, probably reactive 4suspicious lymphoid infiltrate, probably lymphoma 5MALT lymphoma

52 MALT lymphoma Immunohistochemistry No specific MALT lymphoma marker  Positivity: CD20, CD79a; Ig light chains; Ig heavy chains: IgM; CD43  Negativity: CD5, CD10, bcl6, IgD, cyclin D1  CD21, CD10, Ki-67: residual lymphoid follicles

53 Differential diagnosis of MALT lymphoma  HP gastritis Wotherspoon criteria spectrum 0-5  other lymphomas: DLBCL, MCL, FL… Integrated approach favoring MALT lymphoma:  dense lymphoid infiltrate  prominent LEL  Dutcher bodies  infiltration of muscularis mucosae  atypia of lymphoid cells  B - cell monoclonality

54 B-cell monoclonality detection Monoclonal IgH rearrangement Polyclonal IgH rearrangement  Imunohistochemistry - Ig light chains  Molecular biology - PCR - IgH rearrangement

55 It is often not possible to establish a clear diagnosis in a single biopsy. repeat the biopsy; sampling ? MALT lymphoma/gastritis? Large cell component? Correct diagnosis and treatment Interdisciplinary communication Repeated biopsies, specialized methods

56 MALT lymphoma after therapy Response: regression of lymphoid infiltrate and LEL Gastric mucosa: atrophy, intestinal metaplasia, empty, fibrotic, basal lymphoid aggregates Always assess Helicobacter pylori B-cell clonality assessment by PCR: not clear

57 Průkaz monoklonality Imunohistochemie lehké řetězy Ig Molekulární genetika PCR přestavba genu IgH CDR III

58 Gastric MALT lymphoma Recurrent genetic abnormalities t(11;18)(q21;q21)/ API2-MALT1 usually the sole genetic abnormality, 25% of g. MALT l., H. p. neg., no response to ATB t(14;18)(q32;q21)/ IgH-MALT1 non-gastric t(1;14)(p22;q32)/ IgH-BCL10; t(1;2)(p22;p12) Different strains of Helicobacter pylori

59 MALT l. in other sites than the stomach Eye – Chlamydia psittaci Skin – Borrelia burgdorferi IPSID – Campylobacter jejuni Salivary, thyroid, lung, orbit, breast, skin Localized; disseminated (30%, after a long period) 5 y OAS: 90%

60 Multiple lymphomatous polyposis Mantle cell lymphoma Follicular lymphoma MALT lymphoma

61 Mantle cell lymphoma  Multiple lymphomatous polyposis  M  60  bad prognosis  imunohistochemistry  genetics WHO

62 Mantle cell lymphoma - localisation Lymph nodes, Waldeyer; bone marrow Extranodal sites: GIT, skin, others GIT: multiple lymphomatous polyposis (MCL, FL, MALT l.)

63 Mantle cell lymphoma CD5 Cyclin D1

64 MALT? MCL? FISH t(11;14)(q13;q32)

65 Enteropathy-associated T-cell lymphoma Proximal jejunum Very rare x most common GI T-cell lymphoma  Acute abdomen (40%) – emergency surgery Obstruction/perforation, peritonitis, sepsis, death  Non-acute: pain, weight loss, malabsorption Age 60, M=F

66 Enteropathy-associated T-cell lymphoma Striking association with celiac disease Histology and immunomorphology  Anaplastic/pleomorphic (80%) Celiac dis.+, enteropathy +, CD56-  Monomorphic (20%) Celiac dis.-, enteropathy+/-, CD56+ Half of the patients die soon after the manifestation

67 Enteropathy-associated T-cell lymphoma Anaplastic T-cells, plasma cells, eosinophils CD3


69 Testicular lymphomas

70 Lymfomy varlete Primární x sekundární 1% všech NHL 2% nádorů varlete ! nejčastější nádor varlete u mužů  50 let !

71 I. Dospělí: DLBCL MALT lymfom, folikulární lymfom T-lymfomy T/NK – lymfomy, nosní typ plasmocytom II. Děti: před pubertou Sek. (5% systém.): Burkitt, DLBCL, lymfoblastické nádory Primární: folikulární lymfom

72 Infiltrace varlete parciální celková Zvětšení  unilaterální  bilat. současné

73 Intertubulární růst DLBCL

74 Destrukce tubulů, difúzní růst

75 Cytologické rysy Nejčastěji: dif. velkobuněčný B-lymfom - CB, IB - CD20+, CD79a+ Stadium IE

76 Lymfom varlete (DLBCL) ! nejčastější nádor varlete u mužů  50 let ! primární diagnózy: 10% chybné („seminom“)

77 Většinou diagnostikován v KLIN. ST. IEA Prognóza nemocných není tak dobrá, jako u odpovídající rizikové skupiny nodálního DLBCL Pozdních relapsy: CNS, druhostranné varle, zejména u nemocných nedostatečně léčených v úvodu

78 The mysterious link between the brain and the testis

79 CNS lymphomas

80 Primární lymfomy CNS pouze v CNS mozek 1% intrakraniálních nádorů – 1% NHL imunodeficientní x imunokompetentní

81 Multifokální, periventrikulární or unifocal mass MR

82 Perivask. manžety RETIKULIN CD20

83 Predispozice imunitní deficity  AIDS EBV-LMP

84 Vzácné prezentace lymfomů v NS Lokalizace Oko Dura mater Mícha, extradurální expanze Lymphomatosis cerebri Kraniální a periferní nervy Typ lymfomu T-lymfom, ALCL intravask. lymfom SLL, MgZL, FL, PTLD

85 Závěr: primární lymfom CNS  svébytná nádorová jednotka  histopatologická diagnóza  stereotaktická biopsie

86 Intravaskulární B-lymfom


88 Lymfoproliferace u imunodeficitů

89 immunodeficiencies Associated tumors Skin, urogenital tract, lymphomas

90 Stavy se sníženou imunitou 1. iatrogenic immunosuppression after transplantation (posttransplantation lymphoproliferative disease, PTLD) 2. autoimmune diseases (RA, SLE) 3. HIV 4. primary immune deficiencies 5. senile EBV-related B-cell lymphomas

91 PTLD Posttransplantation lymphoproliferative disease Clinicopathological spectrum 1. Histol. Iniciální - časné 2. Polymorfní 3. Monomorfní 4. Hodgkinův lymfom, PTLD podobná Hodgkinově lymfomu

92 Etiopatogeneze imunosuprese infekce EBV chronická antigenní stimulace štěpem další infekční agens?

93 EBV Polyklonální lymfoidní proliferace Klonální populace Sekundární genetické změny „IM“ Plazmocytární hyperplazie Polymorfní PTLDMonomorfní PTLDHL Reaktivní T-buňky Klesající imunitní odpověď Vliv EBV

94 PTLD – potransplantační lymfoproliferace Early – up to 1 year – EBV - strong role Late – after 1 year

95 Frekvence PTLD: 1-10% - typ a stupeň imunosuprese, - EBV status Lokalizace: často extranodální Nejvíce: 1. rok po transplantaci PTLD časná x pozdní Mortalita: Tx solidních orgánů: 60% kostní dřeně: 80% Reverzibilita: u některých PTLD Původ: příjemce (solidní) x dárce (BMT)

96 EBV Infectious mononucleosis Burkitt lymphoma Hodgkin lymphoma B-cell lymphomas in immunosuppressed patients (HIV, transplantation) Nasopharyngeal carcinoma

97 HIV and lymphomas 1 st most frequent tumor: Kaposi sarcoma 2nd: lymphomas Lymphoma - AIDS defining illness 3% of patients with AIDS

98 Lymfomy u HIV pozitivních lidí  agresívní B-lymfomy, často extranodální; heterogenní (GIT, CNS)  patogenetické faktory: herpesviry: EBV (v 50%), Kaposi Sarcoma Human Virus/HHV 8 (primary effusion lymphoma) chronická antigenní stimulace genetické abnormality poruchy cytokinové regulace  prognóza závisí na tíži imunodeficience

99 Lymphomas associated with HIV Incidence increased: 60-200 x (versus noninfected population) Incidence decreases with HAART, ↑CD4 Hodgkin lymphoma: AIDS: risk 10 x higher

100 Lymfomy u HIV+ 1. lymfomy postihující také imunokompetentní pacienty časté: Burkittův (klasický, plazmacytoidní, atypický), DLBCL (často v CNS!) vzácnější: extranodální B-lymfom z marginální zóny, periferní T-lymfom, klasický Hodgkinův lymfom 2. lymfomy specifické pro HIV+ pacienty primary effusion lymphoma, plazmoblastický lymfom ústní dutiny 3. léze vyskytující se i u jiných imunodeficiencí - polymorfní "PTLD"

101 Lymfoproliferativní choroby u primárních imunodeficiencí  rare More than 60 PID Heterogenous Manifestattion highly variable Ataxia teleangiectasia Wiskott Aldrich sy CVID SCID XLP…

102 Lymfoproliferativní choroby u primárních imunodeficiencí  hlavně u dětí, častěji u chlapců; (x common variable immunodeficiency: dospělí)  většinou extranodální (GIT, CNS)  většinou B-lymfoproliferace: fatální infekční mononukleóza, DLBCL, lymfomatoidní granulomatóza, Hodgkinův lymfom; T-lymfomy /leukémie

103 Senile EBV+ lymphoproliferations no other overt ID, only the age… Oyama AJSP 2003

104 EBV + senile lymphoproliferations Rare Asia over 50 Various histological appearance


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