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Lymphoma lecture(1)
- 2. Normal lymph node architecture Cortex Medulla Plasma cells Paracortex T-cells Lymphoid Follicle B-cells Lymphocyte constantly recirculate
- 3. Lymphoid follicle (B-Cell region) Germinal center Centroblasts, centrocytes Mantle and marginal zones
- 4. Small centrocyte-arrowhead, large centrocyte-arrow, centroblast - thick arrow Mitosis – curved arrow Germinal center cells
- 5. LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS Summary of lymph node pathology
- 6. Clinical manifestations of lymph node diseases -Enlarged -Tender/non tender -Systemic symptoms
- 7. LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS Summary of lymph node pathology
- 8. reactive changes in the nodes
- 9. Follicular hyperplasia Rheumatoid arthritis, Toxoplasmosis
- 10. Follicular hyperplasia tingible body macrophages Resting lymphocytes in the mantle zone
- 11. Interfollicular/paracortical hyperplasia T-cell response, acute viral infections(mononucleosis)
- 12. Sinus histiocytosis Dilated sinusoids, increased number and size of cells lining the sinusoids
- 13. Toxoplasmosis pink, epitheloid macrophages, follicular hyperplasia Mixed type lymphadenopathy
- 14. Necrotizing lymphadenitis Microabscesses Bartonella Henselae (silver stain) cats scratch
- 18. Lymphadenopathy (cont) LYMPHADENOPATHY BENIGN NEOPLASTIC PRIMARY: LYMPHOMA SECONDARY: METASTASIS
- 19. ·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 …”
- 20. Lymphoma classification Rappaport 1966 Lukes Collins 1974 Working formula 1982 Kiel 1988 REAL 1994 WHO 2001 2008 Is this the REAL thing…..? WHO ……knows!
- 21. 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%) ·
- 22. Etiology of lymphomas Translocations involving the IgH are requent
- 23. 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 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. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 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 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- 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) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- 35. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Nucleated erythrocyte Spherocytes Smudge cells Small lymphocytes
- 36. 3.Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 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
- 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
- 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 10th edition Ackerman histopathology text book 11th edition Deciy text book of hematology