1. Diagnostika lymfomůExtranodální lymfomy Doc. MUDr. L. Boudová, Ph. D.

2. Contents WHO Classification 2008

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

4. Lymphoid malignanciesEpidemiology 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. Lymphoma diagnosismolecular biology 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)

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. Diffuse large B-cell lymphoma 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 lymphomaDifferential 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 CD20 Diffuse/ vaguely nodular 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?

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 lymphomaclinicopathological 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

31. BCLUWFIBDLBCLACHL

32. BCLUWFIBDLBCLACHLDLBCL vs. CHLmorphology, IHC Garcia, Histopathology 2005

33. BCLUWFIBDLBCLACHLDLBCL vs. CHLmorphology, IHC Traverse-Glehen AJSP 2005

34. DLBCL Differential diagnosis versus Burkitt lymphoma

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

36. BCLUWFIBDLBCLABL

37. BCLUWFIBDLBCLABLDLBCL versus Burkittmorphology, 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 symptomyčasto 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

44. DLBCLHE CD20

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

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