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WBC related disease part II

WBC related disease part II. 嘉義基督教醫院 李明陽醫師. WBC disease part II. Malignant lymphoma CLL Plasma cell disorder. LN paracortex. LN medulla. IgM. B-CLL/SLL. Plasmacytoid Lymphocyte . B-immunoblast. Blood Marrow Primary follicle. Precursor B ALL/LBL. Lymphoplasmacytic lymphoma .

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WBC related disease part II

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  1. WBC related disease part II 嘉義基督教醫院 李明陽醫師

  2. WBC disease part II • Malignant lymphoma • CLL • Plasma cell disorder

  3. LN paracortex LN medulla IgM B-CLL/SLL Plasmacytoid Lymphocyte B-immunoblast Blood Marrow Primary follicle Precursor B ALL/LBL Lymphoplasmacytic lymphoma Large B-cell lymphoma BM A N T I G E N cIgM+CD20+ Plasma cell Myeloma Follicular lymphoma t(14;18) CD23+ Bcl-2 CD19 CD10 TdT Cu+ Centrocyte BM IgM+ Precursor B Lymphoblast Naïve B IgG/A CD20- CD38+ CD20+,CD5+,sIgM+D+ CD10+ Bcl-6 Burkitt’s lymphoma t(8;14) IgM+G+ Centroblast CD23- Plasma cell Mantle cell Marginal Zone & Monocytoid B cell Mantle cell lymphoma t(11;14) Large B-cell lymphoma Marginal Zone Lymphoma t(11;18) Germinal center

  4. The Differentiation Stage of B & T-cells Determined the Type of Malignancy Early Pre-B Pre-B Mature-B Immuno- blast Lympho- Plasmacytoid Plasma cells BM Lymph nodes or lymphoid tissues BM Y sIgM sIgM/G/A sIgM/G/A sIgM/D Y Y Y Y Y Y Y Y Y HCR HCR KR/D λR/D Prothymocyte Medullary T (peripheral T) Subcapsular T Cortical T CD7 CD2 CD5 CD3 CD1 CD4/8 Precursor T-cell leukemia/lymphoma Peripheral T-cell neoplasms

  5. Classification of Lymphoma 1982 • Working formulation • Low grade (LG) • Intermediate grade (IG) • High grade (HG) 1994 • Revised European-American Lymphoma (REAL) • Emphasize Immunophenotype 2001 WHO classification

  6. Precursor B Lymphoblastic leukemia/lymphoma Mature B Chronic lymphocytic leukemia/Small lymphocytic lymphoma Pro-lymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B lymphoma Hairy cell leukemia Plasma cell myeloma Monoclonal Gammopathy of undetermined Significance (MGUS) Solitary plasmacytoma of bone Extraosseous plasmacytoma Primary amyloidosis Heavy chain diseases Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma) Nodal marginal zone B-cell lymphoma 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/leukemia B-cell proliferations of uncertain malignant potential Lymphomatoid granulomatosis PTLD, polymorphic WHO Hisological Classification of B-cell Neoplasms

  7. Leukemic/disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell leukemia/lymphoma Cutaneous Mycosis fungoides Sezary syndrome Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Other extranodal Extranodal NK/T cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Nodal Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, unspecified Anaplastic large cell lymphoma Neoplasm of uncertain lineage and stage of differentiation Blastic NK cell lymphoma WHO Histological Classification of T-cell and NK-cell Neoplasms

  8. Cellular Origin of Lymphoma NHL HL B-lymphocytes 80~85% T-lymphocytes 13~14% NK-cells 1~2% 30% U.S. & Europe B-lymphocytes 55~60% T-lymphocytes 40~45% NK-cells ?% Taiwan 10% Immune deficiency Autoimmune disorder Infection Autoimmune disorder Infection ? Possible etiologies ?

  9. Frequency of B and T/NK Cell Lymphoid Malignacies (WHO) • Diffuse large B-cell lymphoma 30.6% • Follicular lymphoma 22.1% • MALT lymphoma 7.6% • Chronic Lymphocytic LeukemiaL/SLL 6.7% • Mantle cell lymphoma 6.0% • Mediastinal large B-cell lymphoma 2.4% • Burkitt’s lymphoma 2.5% • Nodal marginal zone lymphoma 1.8% • Lymphoplasmacytic lymphoma 1.2% • Mature T-cell lymphomas 7.6% • Anaplastic large cell lymphoma 2.4% • Precursor T lymphoblastic 1.7% • Other types 7.4%

  10. Symptoms and signs • Lymphadenopathy • Fever • Body weight loss • Night sweat • Organ-specific • Diagnosis • Biopsy for Pathological exam • Staging work up

  11. Staging of HL(Cotswold revision of the Ann Arbor staging classification) A, no symptoms; B, fever/sweats/weight loss; X, bulky disease:>1/3 widening of the mediastinum at T5-6, or maximun of nodal mass>10cm E, involvement of a single extranodal site

  12. A: no symptoms B: fever/sweats/weight loss; X: bulky disease:>1/3 widening of the mediastinum at T5-6, or maximun of nodal mass>10cm E:indicates extranodal involvement adjacent to an involved lymph node (eg, disease of mediastinal nodes and hilar adenopathy with adjacent lung infiltration is classified as stage IIE)

  13. International Prognostic Index for NHL Five clinical risk factors:  1. Age >   60 years  2. Serum LDH elevated  3. Performance status >  2 (ECOG) or <   70 (Karnofsky)  4. Ann Arbor stage III or IV  5. >1 site of extranodal involvement Patients are assigned a number for each risk factor they have Patients are grouped differently based upon the type of lymphoma For diffuse large B cell lymphoma:  0,1 factor = low risk: 35% of cases; 5-year survival, 73%  2 factors = low-intermediate risk: 27% of cases; 5-year survival, 51%  3 factors = high-intermediate risk: 22% of cases; 5-year survival, 43%  4,5 factors = high risk: 16% of cases; 5-year survival, 26%

  14. Treatment • anti-CD20 (Rituximab) • anti-CD20 radioimmunoconjugates: • Y (Yttrium)-90 ibritumomab tiuxetan (Zevalin) • I-131 tositumomab (Bexxar • anti-CD52 (Alemtuzumab, Campath-1H) • Gold standard: • Systemic chemotherapy • Combination chemotherapy • CHOP • m-BACOD • ESHAP • BOMES • BEAM (myeloablative) • +Autologous stem cell transplantation • Purine analogue • Fludarabine Radiotherapy 13-cis-Retinoid acid

  15. WHO Histological Classification of Hodgkin Lymphoma • Nodular lymphocyte predominant HL (NLPHL) • Classical HL (CHL) • Nodular sclerosis classical HL (NSCHL) • Mixed cellularity classical HL (MCCHL) • Lymphocyte-rich classical HL (LRCHL) • Lymphocyte-depleted classical HL (LPCHL)

  16. Common Clinical Characteristics of Hodgkin Lymphoma • Neck lymphadenopathy • Young adult • Hodgkin and Reed-Sternberg cells (HRS) • Rich inflammatory backgroud

  17. Monomorphic small and round B-lymphocytes in PB/BM/LN Median age of 65 Male/female=2/1 Most asymptomatic Transform to DLBCL (Richter syndrome), 3.5% Rai classification (stage I, II, III, IV) or Binet classification ( stage A,B,C) Trisomy 12 and 13q, 14q abnormality CD5 (+), CD 23(+) Indolent but incurable Median OS, 7 years Survival : normal karyotype > trisomy 12 > 13 q > 14q Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

  18. Lymphoplasmacytic lymphocytes in PB/BM/LN/Spleen Serum M-protein with hyperviscosity and cryoglobulinemia 1.5%, male predominant Organomegaly, coagulopathy, neuropathy, plasmapheresis/ exhange should be considered Association with HCV infection DDX with CLL, marginal zone lymphoma (MALToma) and follicular lymphoma Rearrangement of PAX-5 gene; t(9;14) Indolent course Aged, advanced stage, cytopenias, neuropathy, weight loss have poor prognosis Lymphoplasmacytic Lymphoma/Waldenström macroglobulinemia

  19. Plasma cell Myeloma • Plasmacytosis • Osteolysis • M-protein • Nephropathy • Incurable

  20. Plasma cell Myeloma-Natural History Acceleration IgG 40% IgA 25% Light-chain 20% Others 15% Diagnosis Tumor burden Poor prognostic factor Monosomy 13 or 13q- Hypodiploidy Tx M+P VAD Treatment Plateau HDCT with AutoPBSCT MGUS II 3 7 -5 -2 0 Time (yr)

  21. Bortezomib phase III trail • APEX ( Assessment of Proteasome Inhibition for Extending Remissions) • 669 patients enrolled: randomly received either dexamethasone or bortezomib • Bortezomib showed significantly increased survival rates among patients (80%) after 1 year, dexamethasone (66%) • 38% response rate for bortezomib • 18% response rate for dexamethasone

  22. Bortezomib as a Model Drug • First proteasome inhibitor • Inhibits 26S proteasome: principle regulator of intracellular protein degradation • The proteasome normally degrades IKB which activates NFKB which then promotes cell survival, stimulates growth, makes cells resistant to apoptosis and importantly induces drug resistance in myeloma cells • Bortezomib prevents all from happening by inhibiting the proteasome

  23. in Mantle Cell Lymphoma • Cancerous cells growing out of control in the lymph nodes • Accounts for only 6% of the non-Hodgkin’s lymphomas • December 6, 2006 FDA approved bortezomib for treatment of patients with mantle cell lymphoma who have received at least one prior therapy • Overall response rate 31% • Complete responses 8% • Median response duration 15.4 months

  24. Non-Hodgkin Lymphoma

  25. Large B lymphoid cells Broad age distribution Male/female=1/1 Nodal (60%) vs. extranodal (40%) Extranodal, common in GI (stomach or ileocoecal region), and any sites elsewhere Pan-B markers, CD5(-), CD10(-) Ki-67+/bcl-6+ Recently, a molecular typing by using microarrays: GC-B (better outcome) vs. activated B (worse outcome) Aggressive course, potentially curable International Prognostic Index (Age, LDH, PS, Stage, Extra-LN) Diffuse Large B-cell Lymphoma

  26. An aggressive B-cell lymphoma with frequent extranodal involvement and leukemic change (L3/ALL) Children & young adults with male predominance Jaws and facial bones in endemic BL, abdominal masses in sporadic BL; rare nodal involvement CNS involvement is quite common Short doubling time of the tumor Infectious rates of EBV (co-factor) Abnormalities of cMYC gene (8q24) play an essential role t(8;14), t(2;8), t(8;22) CD5(-), CD10(+), Pan B Ag(+) Highly aggressive, potentially curable after high dose C/T Burkitt Lymphoma

  27. B-lymphoblastic lymphoma • Distinguish from ALL : • PB invlvement (-) • BM: < 25% blast • Extramedullary tumor donimant • TdT(+) , CD 10+, CD 34+ , CD19+ • t(9.22)  poor outcome

  28. Follicular centre B cells Median age of 59 years Male/female=1:1.7 Nodal disease, also in Spleen/PB/BM(40%) Histology pattern: follicular(>75%), follicular and diffuse(25~75%), minimally follicular(<25%) Histology grade I ,grade II , grade III Transform to diffuse large B-cell lymphoma is occassionally seen Rearrangement of Ig with extensive somatic mutations and intraclonal diversity (GC cells) t(14;18)(most cases)(BCL-2 overexpression)& t(2;18)(less cases) Follicular Lymphoma

  29. Extranodal B-lymphoma with heterogenous* B lymphocytes GI tract(50%), followed by lung, head and neck, ocular, skin, thyroid, and breast epithelial associated Median age of 60 years Male/female=1:1.2 Association of chronic inflammation, infections, (Helicobacter pylori, Borrelia burgdorferi) autoimmune diseases Antibiotics treatment, chemotherapy, surgical intervention Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue (MALT lymphoma) *. Small lymphocytes, centrocytes, monocytoid, centroblasts, immunoblasts, plasmacytoid lymphocytes

  30. Expansion of marginal zone B (mostly monocytoid) cells without evidence of extranodal or splenic involvement Uncommon Rare trisomy 3 and t(11;18) as seen in MALToma Indolent lymphoma Poor response to chemotheray Median OS, 5 years Nodal Marginal Zone B-cell Lymphoma

  31. Small lymphocytes involve the red and white pulp, with some transformed large cells, and with/without circulating polar villous lymphocytes Male/female=1/1 Age>50 years Involvement of spleen/BM/PB, rarely LN M-protein (30%) Splenomegaly, autoimmune anemia or thrombocytopenia Deletion of 7q21-32 Trisomy 3 and t(11;18) in extranodal MZL, but not in SMZL Indolent course, poor response to chemotherapy Splenctomy is considered Splenic Marginal Zone Lymphoma

  32. Small B lymphoid cells with oval nuclei, abundant cytoplasms with hairy projections in BM/Spleen red pulp/PB 2% of lymphoid leukemia Median age of 55 years Male/female=5/1 Splenomegaly, pancytopenia with monocytopenia, infections, vasculitis and immune dysfunction BM histology, “fried egg” appearance and reticulin fibrosis HCL variant Purine analogues (2-chlorodeoxyadenosine, deoxycoformycin, IFN, and splectomy are the choice of treatment Hairy Cell Leukemia

  33. Small to medium sized lymphocytes resemble the centrocytes/FCC, with absence of transformed cells seen in FL Median age of 60 years Male/female=2/1 LN/SN/BM/GI/ Waldeyer’s ring/PB Rearrangement of Ig without somatic mutations (pre-GC cells) t(11;14)(q13;q32) IgH/CYCLIN D1 Blastoid variant (classic vs. pleomorphic) with aggressive course Incurable with median OS, 3~5 years if no aggressive tx Mantle Cell Lymphoma

  34. A subtype of DLBCL, arising from mediastinum of putative thymic B-cell origin 30~40 years with female predominance Large anterior mediastinal masses, dissemination will occur EBV- Large B lymphoid cells in remnant thymic tissues with compartmentalising fibrosis CD19+/CD20+/CD10-/CD5-/CD30±/CD45+ Overexpression of REL gene (9p) and MAL gene Lack of bcl-2, bcl-6, & MYC Good response to C/T±R/T Px, dependent on initial stage Mediastinal (thymic) Large B-cell Lymphoma

  35. A subtype of extranodal DLBCL limited in the small vessels No known epidemiology (adults only till now) Widely disseminated in extranodal sites at presentation Symptoms of skin and CNS, variable organ involvements CD45+/CD20+/CD19+/CD22+/CD79a+ Aggressive lymphoma and poor response to chemotherapy Intravascular Large B-cell Lymphoma

  36. Body cavity (serous)-based lymphoma HHV-8 Immunodeficiency (HIV+) Rare EBV (co-infected) Immunoblastic, Plasmablastic, Anaplastic CD45+/CD19-/CD20-/CD79a-/CD30+ /CD38+/CD138+/c&sIg- Primary Effusion Lymphoma • Germinal or Post-germinal center B cell (? Some from naïve B cells • Poor prognosis(< 6m) despite the chemotherapy • Antiviral treatment and proteosome inhibitors

  37. Surface Marker Analysis of B-Lymphoid Malignancy

  38. T cell lymphoma/leukemia

  39. T-lymphoblasts in PB/BM(T-ALL, 15% of ALL), in nodal or extranodal sites(T-LBL, 90% of LBL) High counts and mediastinum or tissue masses TdT+/cCD3+/CD2+/CD7+/ CD5+/CD1a+/CD4+CD8+ Rearrangement of TCRαandδ(14q11),β(7q35), and γ(7p15), with partners of MYC(8q24), TAL1(1p32), RBTN1(11p15), RBTN2(11p13), and HOX11(10q24) Rather unfavorable clinical outcome than B-ALL/LBL Precursor T lymphoblastic leukemia/lymphoma

  40. T-PLL, rare Hepatosplenomegaly, lymphadenopathy with cytopenias, skin involvement in 20% Small to median-sized lymphocytes with cytoplasmic protrusions or blebs TdT-/CD1a-/CD2+/CD3+/CD7+/CD4+8(60%),CD4+8+(25%), CD4-8-(15%) t(14;14)(q11;q32) Aggressive course Median OS < 1 year CAMPATH-1 responsive T-cell Prolymphocytic Leukemia

  41. NK-cell proliferation Rare, but more prevalent in Asians Teenagers with male predominance PB/BM/LV/SN Fever, constitutional symptoms, a leukemic blood picture, coagulopathy, and hemophagocytic syndrome, as well as organ failure EBV+/hypersensitivity to mosquito bites CD2+/CD3-/CD56+/CD11b±/CD16 ±/CD57- No TCR rearrangement Rapid progress with fatal outcome within 1~2 years Aggressive NK-cell Leukemia

  42. HTLV-1 related peripheral T-cell (flower cells) neoplasm Endemic in Japan Median age of 55 years with male/female=1.5/1 PB/BM/LN/Skin(Pautrier-like microabscess) Acute, lymphomatous, chronic and smoldering variants P40 tax viral protein leads to transcriptional activation of many genes in the HTLV-1+ lymphocytes CD2+/CD3+/CD5+/CD25++ CD7-/CD4+CD8-(rare, CD4-CD8+) Clinical subtypes, performance status, age, Ca, LDH levels are prognostic factor In acute form, median OS=1~2yrs Treatment choice: INF + AZT +C/T(?) Adult T-cell Leukemia/Lymphoma

  43. More prevalent in Asia, Mexico, Central and South America Adults and male predominant Extranodal presentations Nasal obstruction, epistaxis due to locally advanced tumor mass Dissemination will occur during the clinical course Strong association with EBV in Asians Angiocentric, angiodestructive with coagulative necrosis CD2+/sCD3-/CD56+/cCD3+/granzyme B+/TIA-1+/perforin+ CD4CD8/CD5/TCR/CD16/CD57/CD43/CD45RO are all negative TCR rearrangement, germline Variable clinical courses, limited vs. disseminated Extranodal NK/T-cell Lymphoma, nasal type

  44. Mature T-cell lymphoma presenting in skin Small to medium-sized cells with cerebriform nuclei Adults/elderly, male/female=2/1 Skin, extracutaneous dissemination may occur Initial patches, plaques on the trunk Epidermotropic infiltration with Pautrier microabscess, and dermal infiltration CD2+/CD3+/CD5+/CD4+/CD8- CD7-/HECA antigen+ Clinical stage, the most important prognostic factor Mycosis fungoides Stage characteristics Ia Skin, limited patches/plaques Ib Skin, disseminated lesions Ic Skin, tumor formation II LN enlargement, histology – III LN enlargement, histology + IV Visceral dissemination

  45. PTCL, systemic involvement with proliferation of endothelial venules and follicular dendritic cells (CD21+ cells) Middle age, male/female=1:1 Generalized LAPs, hepatosplenomegaly, and skin rashes, BM is commonly involved Advanced stage at diagnosis, systemic symptoms, and hypergammaglobulinemia, serositis with effusions EBV+ in adjacent B cells (>75% cases) T-zone hyperplasia of LN, with a lot of reactive cells, included transformed immunoblastic B cells, and esp. FDCs CD2+/CD3+/CD5+/CD4+CD8+/CD7- Aggressive course with a median OS < 3 years Angioimmunoblastic T-cell Lymphoma(ALIT)

  46. Half of the PTCL in Western countries Adults, male/female=1/1 LN/LV/Spleen/Skin Systemic symptoms and paraneoplastic features Lymphoepithelioid cell variant (Lennert lymphoma) CD2+/CD3+/CD5+/CD4+CD8-/CD30± Complex cytogenetic changes, trisomy 3 Poor prognosis, 5-yr SR=20~30% Clinical stage and IPI, as prognostic factors Peipheral T-cell Lymphoma, unspecified

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