Lymphoma lecture(1)

short review of lymphomas !!

1. 1 Lymphoma by Dr.Hayelom k Final year Pathology resident Jimma university medical center [email protected]

2. Lymphocytes in different phases of maturation ???

3. Normal lymph node architecture Cortex Medulla Plasma cells Paracortex T-cells Lymphoid Follicle B-cells Lymphocyte constantly recirculate

4. Lymphoid follicle (B-Cell region) Germinal center Centroblasts, centrocytes Mantle and marginal zones

5. Small centrocyte-arrowhead, large centrocyte-arrow, centroblast - thick arrow Mitosis – curved arrow Germinal center cells

6. LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS Summary of lymph node pathology

7. Clinical manifestations of lymph node diseases -Enlarged -Tender/non tender -Systemic symptoms

8. LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS Summary of lymph node pathology

9. reactive changes in the nodes

10. Follicular hyperplasia Rheumatoid arthritis, Toxoplasmosis

11. Follicular hyperplasia tingible body macrophages Resting lymphocytes in the mantle zone

12. Interfollicular/ paracortical hyperplasia T-cell response, acute viral infections(mononucleosis)

13. Sinus histiocytosis Dilated sinusoids, increased number and size of cells lining the sinusoids

14. Toxoplasmosis pink, epitheloid macrophages, follicular hyperplasia Mixed type lymphadenopathy

15. Necrotizing lymphadenitis Microabscesses Bartonella Henselae (silver stain) cats scratch

16. Granulomatous lymphadenitis

17. Lymphadenopathy LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS

18. Metastatic adenocarcinoma

19. Lymphadenopathy (cont) LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS

20. ·Willis (1948) “… nowhere in pathology has a chaos of names so clouded clear concepts as in the subject of lymphoid tumors ….” •Hopwood (1957) “… the urge to classify is a fundamental human instinct: like a predisposition to sin, it accompanies us into the world at birth and stays with us to the end …”

21. Lymphoma classification Rappaport 1966 Lukes Collins 1974 Working formula 1982 Kiel 1988 REAL 1994 WHO 2001 2008 Is this the REAL thing…..? WHO ……knows!

22. WHO Classification of lymphomas At least 30 types of lymphoma are recognized 3 broad flavors - B-cell lymphomas Precursor (immature), peripheral (“mature”) - T-cell lymphomas - Hodgkin lymphoma ( bona fide lymphoma) ~ 85% in North America and Europe are B-cell · two types account for > 50% of lymphomas - diffuse large B- cell lymphoma (~ 30 - 40%) - follicular lymphomas (~ 25 - 30%) ·

23. Etiology of lymphomas Translocations involving the IgH are requent

24. Etiology of lymphomas Inherited genetic factors-genomic instability: -Down syndrome, NF type I Autoimmune disorders : Sjogren, Hashimoto Viruses: EBV, HTLV1 and herpes virus Environmental agents: - Chronic inflammation, Helicobacter Pylori and MALT lymphoma -Gluten sensitive enteropathy and intestinal lymphoma Iatrogenic: -Radiotherapy -Chemotherapy

25. Diagnosing lymphomas

26. Diagnosing lymphoid neoplasias HOW ? WHY ? Flow cytometry Immunohistochemistry Karyotyping Diagnosis Monitoring Prognosis

27. Diagnosing lymphomas CD 20 antibody staining B lymphocytes

28. Diagnosing lymphoid neoplasias T-cell markers CD3 mature T cells CD4 – helper T cell CD5 – T cell , small subset of B cells CD8 – cytotoxic T cell B cell markers CD19 - mature B cell CD20 - mature B cell CD23 - activated mature B cell CD10 Bcl-6

29. Lymphoid leukemia versus lymphoma Somewhat arbitrary, distinctions for lymphoid neoplasias Lymphoid leukemia presents with mainly bone marrow and blood involvement Lymphoma presents with nodal or extranodal mass with minimal blood/marrow involvement Many diseases overlap or evolve from one another

30. Signs and symptoms Lymphoid leukemias present with signs and symptoms related to bone marrow involvement Anemia, thrombocytopenia, leukopenia Lymphomas present as nontender mass (>2 cm) Extranodal- skin, GI tract, brain, Fever, weight loss, night sweats (B-symptoms) Patients may have any combination of the above

31. Origin of B-cell lymphomas Marginal zone Mantle zone Germinal center Naive B-cell Mantle cell lymphoma Follicular lymphoma Burkitt lymphoma Large cell lymphoma Memory B-cell CLL/SLL Marginal zone lymphoma Plasma cell Myeloma

32. C hronic L ymphocytic L eukemia/ S mall L ymphocytic L ymphoma CLINICAL •commonest leukemia •CLL often picked up on routine CBC •typically indolent (but not always!) •rare less than 40 years •complications: • autoimmune (10-15%) (ITP, AIHA) • hypogammaglobulinemia • transformation (DLBCL) PATHOLOGY •diffuse growth pattern Spleen is frequently involved

33. proliferation center- mitotically active cells=this is where the tumor cells grow C hronic L ymphocytic L eukemia/ S mall L ymphocytic L ymphoma

34. MORPHOLOGY - small, mature lymphocytes >4000/mm3 - smudge cells characteristic IMMUNOPHENOTYPE CD19, CD20, CD23, CD5 GENETICS 13q deletion (good prognosis) trisomy of 12 11q deletion (bad prognosis) C hronic L ymphocytic L eukemia/ S mall L ymphocytic L ymphoma

35. C hronic L ymphocytic L eukemia/ S mall L ymphocytic L ymphoma Nucleated erythrocyte Spherocytes Smudge cells Small lymphocytes

36. 3. C hronic L ymphocytic L eukemia/ S mall L ymphocytic L ymphoma TRANSFORMATION 1. LARGE CELL LYMPHOMA (Richter) - 10% 2.Prolymphocytic lymphoma -15-30% average survival 1 year

37. FOLLICULAR LYMPHOMA 15-20 000/year, less common in Europe, Asia -Middle age patient’s - Most common indolent lymphoma -Peripheral blood 10% -Bone marrow 85% involved -Spleen and liver also commonly involved -Can undergo transformation into large cell lymphoma

38. Follicular lymphoma Classic low power view - back-to-back follicles - loss of interfollicular zones - extranodal follicles - uniform size of follicles

39. Follicular lymphoma Back to back, uniform follicles, attenuated mantle zone, no tingible body macrophages

40. Follicular lymphoma diagnostic hallmark t(14;18) Translocates the bcl-2 gene next to IgH over expression of bcl-2 prevents apoptosis Bcl-2 + Bcl-2 – staining in normal Lymphoid follicle

41. APOTOSIS (Hippocratic Greek) APOPTOSIS (modern Greek)

42. Follicular lymphoma centrocyte: -cleaved/notched/twisted -raisin -buttock 50% transforms into large cell lymphoma

43. Follicular lymphoma Centroblasts- important in grading

44. Splenic involvement in follicular lymphoma

45. Origin of B-cell lymphomas Marginal zone Mantle zone Germinal center Naive B-cell Mantle cell lymphoma Follicular lymphoma Burkitt lymphoma Large cell lymphoma Memory B-cell CLL/SLL Marginal zone lymphoma Plasma cell Myeloma CB/CC

46. Diffuse Large B-cell Lymphoma Most common non Hodgkin lymphoma(~40%) - 25, 000 new cases/year - median age 6th decade - all age groups - typically present with a single rapidly enlarging mass - often (~ 40%) extranodal Variable clinical outcome aggressive, has to be treated immediately

47. Diffuse Large B-cell lymphoma Etiology and clinicopathologic subtypes - de novo -BCL-6 mutation freezes the differentiation of cells in the germinal center + blocks the effect of p53 -can occur anywhere in the body - transformed from either follicular lymphoma (t14;18) or CLL/SLL - immunosuppressed patients - transplant patients, AIDS patients - KSHV, EBV, HHV-8 infection

48. Diffuse Large B-cell Lymphoma Note the population of large tumor cells, diffuse growth pattern, variation in size and shape of cells, cells with vesicular nucleus and cleaved cells

49. Origin of B-cell lymphomas Marginal zone Mantle zone Germinal center Naive B-cell Mantle cell lymphoma Follicular lymphoma Burkitt lymphoma Large cell lymphoma Memory B-cell CLL/SLL Marginal zone lymphoma Plasma cell Myeloma CB/CC

50. Burkitt’s lymphoma Extremely aggressive , high grade lymphoma T(8;14) activates c-myc oncogene Clinical-genetic classification - endemic - sporadic - immunodeficiency-associated

51. Extremely aggressive high grade lymphoma T(8-14) activates c-myc oncogene Endemic Non-endemic Immunodeficiency children and young adults Site Jaw/Facial Ileocecal area Systemic/ non-CNS EBV ~ 100% ~ 15-20% ~ 25% BM not involved can be can be Cure rate high high ? Burkitt lymphoma

52. t(8;14) which activates c-myc oncogene

53. Burkitt lymphoma endemic variant

54. Burkitt lymphoma small round cells in a “starry sky” pattern created by macrophages engulfing cellular debris, mitoses

55. Clinically: - typically presents in elderly males - frequently extranodal: - leukemic phase - GI: lymphomatous polyposis - much more aggressive than other - poor response to conventional chemotherapy - median survival 3 - 4 years Mantle cell lymphoma

56. • classic cytogenetics [~ 90%]: t(11;14)(q13;q32) upregulates cyclinD1 expression, dysregulates cell cycle immunohistochemically: intranuclear cyclin D1 Origin: CD5 positive, naïve cells of the mantle zone CD19+, CD20+, CD23 - Mantel cell lymphoma

57. Origin of B-cell lymphomas Marginal zone Mantle zone Germinal center Naive B-cell Mantle cell Lymphoma CLL/SLL Follicular lymphoma Burkitt lymphoma Large cell lymphoma Memory B-cell CLL/SLL Marginal zone lymphoma 4.Plasma cell Myeloma CC/CB

58. Extra-nodal marginal zone lymphoma, MALToma Pathogenesis: Autoimmune disorders: thyroid(Hashimoto), salivary glands (Sjogren) Chronic infection: stomach, lung, skin, conjunctiva Begins as a polycloncal reactive process, over time becomes a monoclonal B cell lymphoma In stomach, highly associated with helicobacter pylori monocytoid B cells, plasma cells, germinal centers, lymphoepithelial lesions Survival : indolent in early stages Cell of origin : marginal zone B cell

59. MALTOMA Gastric MALToma

60. Origin of B-cell lymphomas Marginal zone Mantle zone Germinal center Naive B-cell Mantle cell lymphoma Follicular lymphoma Burkitt lymphoma Large cell lymphoma Memory B-cell CLL/SLL Marginal zone lymphoma 4.Plasma cell Myeloma CC/CB

61. typically presents as: - male in 6th decade - splenomegaly - no lymphadenopathy - CBC: - pancytopenia - marked monocytopenia • splenic disease: - red pulp (unique ) Hairy cell leukemia

62. Hodgkin lymphoma Incidence - ~ 1% of all new cancers in USA - ~ 7,500 new cases/year - constant recent increase Age - bimodal age-curve (unique in cancer) - 15 - 35 - > 50 Sex - M:F = ~ 4:3 (except nodular sclerosis)

63. Hodgkin Lymphoma • Painless lymphadenopathy - cervical ~ 70% - axillary ~ 15% - inguinal ~ 10% • Constitutional symptoms - fever - night sweats - weight loss • Infections : fungal, TB

64. unique amongst cancers: rarity of the neoplastic cell in involved tissue DIAGNOSTIC REED-STERNBERG CELL or variants Pleomorphic cellular infiltrate: - lymphocytes - macrophages - plasma cells - eosinophils - fibroblasts - neutrophils • predominate • vary according to classification • reactive Hodgkin lymphoma

65. LYMPHOCYTE PREDOMINANT nodular sclerosis mixed cellularity lymphocyte depletion lymphocyte rich 95% 5% Hodgkin lymphoma

66. Hodgkin lymphoma Classic Reed-Sternberg cell

67. Hodgkin lymphoma A B C D A. Classic B. Mononuclear variant C. Lacunar variant D. Lympho-histiocytic variant

68. Hodgkin Lymphoma CD15 and CD30 antibodies are used to stain Reed Sternberg cells

69. Nodular sclerosing Clinical: -adolescent and young adult, -females > males -usually lower cervical, supraclavicular, or mediastinal LN Histology: - occasional R-S cells, Lacunar cells, inflammatory cells, bands of sclerosis Survival: Excellent

70. Hodgkin lymphoma, nodular sclerosing

71. NS MC LD LR Frequency ~70% ~20% <1% ~5% Usual age 15- 30 any/middle >50 any middle Clinically females abdominal advanced early mediastinal splenic marrow stage 5yr survival ~80% ~60% ~30% ~90% Hodgkin lymphoma features

72. Staging of HL I: Single LN region or extra-nodal site II: 2 or more LN regions on same side of diaphragm III: LN on both sides of diaphragm, may include spleen IV: Multiple or disseminated foci Further divided into absence (A) or presence (B) of fever, night sweats, unexplained weight loss of >10% body weight

73. •clinically: - adults - Mycosis fungoides patch, plaque, tumor - Sezary Syndrome - erythroderma - generalized adenopathy - circulating tumor cells - MF: indolent but progressive - SS: unfavorable (10-20%/5 year survival) •pathologically: - classic epidermotropism - papillary dermal fibrosis - cerebriform nuclei •immunophenotype: CD4 T-cell lymphomas

74. Mycosis fungoides Plaque phase tumor phase

75. Sezary syndrome Generalized exfoliative erythroderma

76. Reference Robbins 10 th edition Ackerman histopathology text book 11 th edition Deciy text book of hematology