Hodgkins lymphoma ppt.pptx

Hodgkin Lymphoma Pathology

1. HODGKIN LYMPHOMA PRESENTED BY : DR CHITA SUBBA PGT III MODERATOR : DR KAMAL K CHELLING DR AKASH P BHUYAN ASSISTANT PROF,DEPT OF PATHOLOGY

2. OUTLINE NORMAL STRUCTURE AND HISTOLOGY OF LYMPH NODE HODGKIN LYMPHOMA INTRODUCTION PATHOGENESIS WHO CLASSIFICATION NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA CLASSICAL HODGKIN LYMPHOMA NODULAR SCLEROSIS HODGKIN LYMPHOMA MIXED CELLULARITY HODGKIN LYMPHOMA LYMPHOCYTE RICH HODGKIN LYMPHOMA LYPHOCYTE DEPLETED HODGKIN LYMPHOMA

3. GLOBAL CANCER INCIDENCE

4. STRUCTURE OF LYMPH NODE

5. NORMAL DISTRIBUTION OF LYMPHOCYTE SUBSETS CORTEX – B cells ,few T cells in GC,FDC, tingible body macrophages PARACORTEX – T cells,few Bcells , IDC, immunoblast,histiocytes,plasmacytoid monocytes MEDULLARY CORDS – Small lymphocytes,plasma cells and immunoblast SINUSES – sinus lining cells and histiocytes

6. FIG:NORMAL B-CELL DIFFERENTIATION AND ITS RELATIONSHIP TO MAJOR B-CELL NEOPLASM

7. FIG:T- CELL DIFFERENTIATION .

8. HODGKIN LYMPHOMA Hodgkin lymphoma was first described by “THOMAS HODGKIN” a British physician in 1832 Studied 7 patients with painless lymphnode enlargement in Guys hospital,London

9. Disease primarily arises in lymph nodes from B-cells and secondarily involves the extra nodal sites it is a disease characterized by heterogenous cellularity comprising of majority of non neoplastic cells with minority of neoplastic cells called REED-STERNBERG cells or HODGKIN CELLS

10. WHO DEFINITION They are composed of large dysplastic mononuclear and multinucleated cells surrounded by a variable mixture of mature non―neoplastic inflammatory cells. Abundant band―like and/or more diffuse collagen fibrosis may be present. The neoplastic cells are often ringed by T cells in a rosette―like manner.

11. PATHOGENEISIS

12. WHO CLASSIFICATION OF HODGKIN LYMPHOMA NODULAR LYPHOCYTE PREDOMINANT HODGKIN LYMPHOMA(NLPHL) CLASSICAL HODGKIN LYMPHOMA (CHL) NODULAR SCLEROSIS MIXED CELLULARITY LYMPHOCYTE RICH LYMPHOCYTE DEPLETED

13. NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA 10% of all Hodgkin lymphoma M:F=3:1 Wide range ,with median age in 30-40 years,unimodal age distribution Localised disease involving peripheral nodes ( cervical,axillary,inguinal ) Relapse: common Indolent disease with excellent survival in most Transformation to DLBCL in minority

14. NLPHL: TYPICAL PATHOLOGIC FEATURES NEOPLASTIC CELLS REACTIVE CELLS OTHERS L&H cell,popcorn cell,LP cell Small lymphocytes,histiocytes,follicular dendritic cells Architecture at least partially nodular Absent/ uncommon:cells with morphology of classic Reed-Sternberg cell Granulocyte and plasma cells sparse to absent Sclerosis uncommon Necrosis absent POSITIVE:CD20,BCL6,CD45,OCT2 bright,BOB1 Lymphocytes in nodules: mostly small polytypic Bcells PTGC may be present in the periphery NEGATIVE : CD15,CD30,EBV T cells :CD4:CD8 ratio may be high Activation of NFkB pathway Normal counterpart:centroblast of germinal center Tfh cells (PD1+,ICOS+)cluster around LP cells Activation of JAK/STAT pathway

15. Lymph node showing vaguely nodular small lymphocyte proliferation Large neoplastic cells with folded /irregular contoured nuclei and small nucleoli in a background of small lymphocyte and histiocyte

16. CD20 OCT2 PD-1

17. NLPHL :VARIATIONS FROM THE TYPICAL CLASSIC AND VARIANT PATTERNS OTHER VARIATIONS A: Classic (B rich ) nodular CD 30 expression by LP cells (usually weak,subset only ,when present) B: Serpiginous /interconnected nodular IgD +,LP cells :patients younger ,almost all male,mostly cervical nodes ,frequent extranodular location of IgD + LP cells C: Nodular with prominent extranodular LP cells Flow cytometry:CD 4/8 double positive T cells D: T cell rich nodular EBV +LP cells (3% cases) E: diffuse with T – cell rich background ;common with recurrences Atypical T cells F: (diffuse) B cell rich pattern Transformation to DLBCL : Greater risk with advanced stage ;splenic involvement Patterns C,D,E and F : Greater chance of advanced stage and of recurrence Risk of transformation to DLBCL :7 % at 10 years,30%at 20 years

18. NLPHL:DIFFERENTIAL DIAGNOSIS Reactive hyperplasia: progressive transformation of GC Classic Hodgkin lymphoma: especially lymphocyte rich CHL T-cell/histiocyte rich large B-cell lymphoma Follicular lymphoma Peripheral T cell lymphoma: High CD4:CD8 ratio(common in NLPHL) T lymphoblastic lymphoma : CD4/CD8 double positive T cells(common in NLPHL)

19. NLPHL :DIFFERENTIAL DIAGNOSIS LYMPHOMA TYPE NLPHL THR/BCL SMALL CELLS Polytypic B cells,T cells,CD4>>CD8,subset CD57+,PD1+ T cells ,including CD8+ and TIA 1+ cells,almost no B cells LARGE CELLS LP cells ,CD20+,BCL 6+ LP cells , centroblast,immunoblast ,RS like cells,CD20+,BCL6+ PATTERN Nodular+/- diffuse Diffuse BEWARE OF SMALL BIOPSIES:DIFFUSE AREAS OF NLPHL CAN BE ALMOST INDISTINGUISHABLE FROM THR/BCL

20. THR/BCL

21. NLPHL:DIFFERENTIAL DIAGNOSIS TYPE OF LYMPHOMA NLPHL FOLLICULAR LYMPHOMA PATTERN Nodules,large,ill defined Follicles,smaller,better delineated SMALL CELLS Small B cells (CD10-,BCL6-,Polytypic )and T cells with rosettes Centrocytes(CD10+,BCL6+ Monotypic )and T cells LARGE CELLS LP cells .CD20+,BCL6+ Centroblast,CD20+,CD10+,BCL 6+

22. FOLLICULAR LYPHOMA

23. CLASSICAL HODGKIN LYMPHOMA 90% OF HODGKIN LYPHOMA Bimodal age distribution,peaks among young adults & elderly adults Usually stage I/II , occasional widespread B symptoms in around 40 % Aggressive but curable 5-year survival in 5%,70 years age Cure in >85% or more ,now

24. CLASSICAL HODGKIN LYMPHOMA REED STERNBERG CELLS AND MONONUCLEAR VARIANTS(HODGKIN CELLS) CD15+/-,CD30+,B-/+(rarely +),Ig -,CD45-,OCT2 and BOB1-,MUM1,ALK1-,EBV + (40% cases) ,PAX5+ BACKGROUND Lymphocytes:T >B ,most cases Histiocytes ,plasma cells,eosinophils,neutrophils : variable proportions Sclerosis,+/- necrosis GENETIC FEATURES Activation/deregulation of NFkB,JAK /STAT,PIK3/AKT and MAPK/ERK pathways,Micro rna alterations.gains of 9p(JAK2) and 2p(REL oncogene)

25. CD 30 CD20 PAX 5

26. NODULAR SCLEROSIS CLASSICAL HODGKIN LYMPHOMA Adolescents and young adults ;F>M Usually, supradiaphragmatic disease (stage I/II) Mediastinum often involved EBV: minority of cases (10-25%)

27. NODULAR SCLEROSIS:MICROSCOPY Nodular growth pattern with broad fibroblast poor birefringent collagen bands surrounding at least one nodule Usually confined within thickened lymphonodular capsule Highly variable numbers of HRS cells, small lymphocytes and other inflammatory cells; often numerous eosinophils, histiocytes and neutrophils; occasional foamy macrophages Mitoses uncommon Lacunar cells

28. CD3 PAX5

29. DIFFERENTIAL DIAGNOSIS Primary mediastinal (thymic) Large B-cell lymphoma COMMON FEATURES: Usually young adults with slight female preponderance B cell origin Ig negative CD30 expression(NSCHL>MLBCL) RS like cells in some MLBCL Sclerosis Similar gene expression Activation of NFkB and JAK/STAT CIITA translocation in subsets (15% on CHL)

30. NSCHL VERSUS MLBCL FEATURE NS HODGKIN LYMPHOMA MLBCL REACTIVE CELLS Reactive cells more numerous ,eosinophils common Fewer reactive cells overall;granulocyte uncommon NEOPLASTIC CELLS Lacunar cells,diagnostic RS cells Oval /lobated cells with pale cytoplasm FIBROSIS Fibrous bands Packeting sclerosis are more common NECROSIS May have neutrophils Granulocyte usually absent NEOPLASTIC CELLS,IMMUNOPHENOTYPE CD15+/-,CD30+,PAX5 +,CD20-/+,CD45-,OCT2/BOB1 - Diffuse strong CD20+,CD45+,CD30-/+,OCT2/BOB1+,CD23+/- PCR IGH PCR usually negative IGH PCR clonal VC SYNDROME uncommon common

31. MEDIASTINAL (THYMIC) LARGE B-CELL LYMPHOMA

32. MEDIASTINAL (THYMIC) LARGE B-CELL LYMPHOMA

33. MEDIASTINAL (THYMIC) LARGE B-CELL LYMPHOMA

34. MIXED CELLULARITY CLASSICAL HODGKIN LYMPHOMA 20-25% of CHL, more frequently in developing countries and HIV+ patients Any age affected ,most common type in older adults ,M;F =2:1 Type of Hodgkin most strongly associated with EBV :75% of cases EBV+

35. MIXED CELLULARITY HODGKIN LYMPHOMA : MICROSCOPY Diffuse or interfollicular proliferation of HRS cells (< 10% of the cellularity) in a reactive microenvironment composed of lymphocytes, eosinophils, neutrophils, plasma cells, histiocytes, fibroblasts. In EBV+ cases, there may be numerous epithelioid histiocytes and even granulomas. Fine interstitial fibrosis may be seen but without collagen broad bands and with no capsular thickening.

36. CD 30 CD15

37. EBV positive in mixed cellularity CHL .EBER (CISH ) strong staining signal in the nuclei of the neoplastic cells

38. LYMPHOCYTE RICH CLASSICAL HODGKIN LYMPHOMA 5% of cases of classical Hodgkin lymphoma M>F(2:1) Localised disease without bulky disease or B symptoms Nodular,rarely ,diffuse growth ,sometimes with remnants of germinal centre Background : resembles that of NLPHL ,easy to mistake for NLPHL Prognosis : slightly better than other CHL, more like NLPHL

39. LYMPHOCYTE RICH HODGKIN LYMPHOMA:MICROSCOPY Two growth patterns: nodular (common) and diffuse (rare) Attenuated T-zone; nodules composed of small lymphocytes, may have eccentric, small or regressed germinal centers ; no eosinophils or neutrophils Some of the HRS cells may resemble LP cells or mononuclear lacunar cells; easily confused with NLPHL. Rarely LRCHL typical nodules surrounded by fibrous bands; maybe classifying as nodular sclerosing classic Hodgkin lymphoma is more appropriate. Coexisting LRCHL and mixed cellularity classic Hodgkin lymphoma possible but rare.

40. LYMPHOCYTE –DEPLETED CLASSICAL HODGKIN LYMPHOMA <2% of cases of CHL Seen in HIV+ patients ,developing countries ;M>F Widespread disease ,peripheral and/or internal lymphadenopathy Immunophenotye as for other CHL:EBV often + Clonal IGH may be found by PCR With optimum treatment, in HIV- patients,prognosis is nearly as good as other CHL patients with same stage of disease

41. LYMPHOCYTE DEPLETED HODGKIN LYMPHOMA :MICROSCOPY Relative predominance of HRS cells and the scarcity of background lymphocytes in relation to the neoplastic cells. 2 patterns: Diffuse fibrosis: Prominent fibroblastic proliferation (nonbirefringent fibrillary stroma) without well formed fibrous bands Numerous histiocytes Scattered Reed-Sternberg cells Scant lymphocytes Lack of plasma cells or eosinophils Reticular: Rich in Reed-Sternberg cells (often sheets) with anaplastic, pleomorphic or sarcomatous features Scant background small lymphocytes Capsular and perinodal infiltration is common

42. CHL:DIFFERENTIAL DIAGNOSIS Reactive lymphoid hyperplasia Non specific reactive hyperplasia Viral lymphadenitis Granulomatous inflammation Non Hodgkin lymphoma T cell/histiocyte rich B cell lymphoma EBV+DLBCL,NOS Peripheral T cell lymphoma Non lymphoid malignancies

43. REACTIVE LYMPHOID HYPERPLASIA

44. INFECTIOUS MONONUCLEOSIS

45. CYTOMEGALOVIRUS LYMPHADENITIS

46. INTERNATIONAL PROGNOSTIC SCORE

47. With current treatment protocols, tumor stage rather than histologic type is the most important prognostic variable. The cure rate of patients with stages I and IIA is close to 90%. Even with advanced disease (stages IVA and IVB), disease-free survival at 5 years is 60% to 70%.

48. MANAGEMENT CHL is now curable in > 85% of cases. Modern polychemotherapy protocols such as ABVD (i.e. doxorubicin, bleomycin, vinblastine, and dacarbazine) and escalated BEACOPP ( bleomycin,etoposide , doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) Stage―adapted treatment In advanced stages, the International Prognostic Score (IPS) is used Novel targeted treatment approaches: CD30―directed antibody-drug conjugate brentuximab vedotin AntiPD1 antibodies

49. THANK YOU