wbc related disease part ii 嘉義基督教醫院 李明陽醫師. wbc disease part ii malignant...
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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
Precursor BLymphoblast Naïve B
ANTIGEN
B-immunoblast
PlasmacytoidLymphocyte
Centrocyte
Plasma cell
Marginal Zone &Monocytoid B cell
Centroblast
LN paracortex LN medulla
BM
Germinal center
BM
BloodMarrowPrimary follicle
Precursor BPrecursor BALL/LBLALL/LBL
B-CLL/SLLB-CLL/SLL
Large B-cell lymphomaLarge B-cell lymphoma
Large B-cell lymphomaLarge B-cell lymphoma
Burkitt’s lymphomaBurkitt’s lymphomat(8;14)t(8;14)
Mantle cell lymphomaMantle cell lymphomat(11;14)t(11;14)
Follicular lymphomaFollicular lymphomat(14;18)t(14;18)
Plasma cellPlasma cellMyelomaMyeloma
LymphoplasmacyticLymphoplasmacyticlymphoma lymphoma
Marginal ZoneMarginal ZoneLymphomaLymphomat(11;18)t(11;18)
CD19CD10TdTCu+
CD23+Bcl-2
Mantle cell
CD23-
IgM+
CD10+Bcl-6
cIgM+CD20+
CD20+,CD5+,sIgM+D+
IgM+G+
IgG/ACD20-CD38+
IgM
The Differentiation Stage of B & T-cells Determined the Type of Malignancy
EarlyEarlyPre-BPre-B
Pre-BPre-B Lympho-Lympho-PlasmacytoidPlasmacytoid
PlasmaPlasmacellscells
BMBM
Immuno-Immuno-blastblast
Mature-BMature-B
Y Y Y Y Y Y YY
HCR HCR KR/D λR/D
sIgM sIgM/D sIgM/G/A sIgM/G/A
BMBM Lymph nodes or lymphoid tissuesLymph nodes or lymphoid tissues
Y Y
ProthymocyteProthymocyte Subcapsular TSubcapsular T Cortical TCortical T Medullary T (peripheral T)Medullary T (peripheral T)CD7
CD2
CD5
CD3
CD1
CD4/8
Precursor T-cell leukemia/lymphoma Peripheral T-cell neoplasms
Classification of Lymphoma
1982• Working formulation
– Low grade (LG)– Intermediate grade (IG)– High grade (HG)
1994• Revised European-American
Lymphoma (REAL)– Emphasize Immunopheno
type
2001
WHO classification
WHO Hisological Classification of B-cell Neoplasms
• 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 Histological Classification of T-cell and NK-cell Neoplasms
• Leukemic/disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic le
ukemia 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, na
sal type
Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-c
ell lymphoma
• Nodal Angioimmunoblastic T-cell lympho
ma Peripheral T-cell lymphoma, unspe
cified Anaplastic large cell lymphoma
• Neoplasm of uncertain lineage and stage of differentiation
Blastic NK cell lymphoma
Cellular Origin of Lymphoma
U.S. &U.S. &EuropeEurope
TaiwanTaiwan
B-lymphocytesB-lymphocytes80~85%80~85%
B-lymphocytesB-lymphocytes55~60%55~60%
T-lymphocytesT-lymphocytes13~14%13~14%
T-lymphocytesT-lymphocytes40~45%40~45%
NK-cellsNK-cells1~2%1~2%
NK-cellsNK-cells?%?%
NHLNHL
Immune deficiency
Autoimmune disorder
Infection
Possible Possible etiologiesetiologies
Autoimmune disorder
Infection ?
HLHL
?
30%
10%
• 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%
Frequency of B and T/NK Cell Lymphoid Malignacies (WHO)
•Symptoms and signs•Lymphadenopathy•Fever•Body weight loss•Night sweat•Organ-specific
•Diagnosis•Biopsy for Pathological exam
•Staging work up
Staging of HLStaging of HL(Cotswold revision of the Ann Arbor staging classification)(Cotswold revision of the Ann Arbor staging classification)
Stage Definition
I Involvement of a single lymph node or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring)
II Involvement of two or more lymph node regions on the same side of the diaphragm; the number of anatomic sites should be indicated by suffix (e.g., II3)
III Involvement of lymph node regions or structures on both sides of the diaphragm
IV Diffuse or disseminated involvement of one or more distant extranodal organ with or without associated lymph node involvement, Involvement of extranodal site(s) beyound those designated E
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>10cmE, involvement of a single extranodal site
A: no symptomsB: fever/sweats/weight loss; X: bulky disease:>1/3 widening of the mediastinum at T5-6, or maximun of nodal mass>10cmE: 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)
International Prognostic Index for NHLFive 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 involvementPatients are assigned a number for each risk factor they havePatients are grouped differently based upon the type of lymphomaFor 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%
Treatment
Gold standard:Systemic chemotherapy
Combination chemotherapyCHOPm-BACODESHAPBOMESBEAM (myeloablative)+Autologous stem cell transplantationPurine analogue
Fludarabine
•anti-CD20 (Rituximab)•anti-CD20 radioimmunoconjugates:
•Y (Yttrium)-90 ibritumomab tiuxetan (Zevalin)•I-131 tositumomab (Bexxar
anti-CD52 (Alemtuzumab, Campath-1H)
Radiotherapy13-cis-Retinoid acid
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)
Common Clinical Characteristics of Hodgkin Lymphoma
• Neck lymphadenopathy
• Young adult
• Hodgkin and Reed-Sternberg cells (HRS)
• Rich inflammatory backgroud
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Monomorphic small and round B-lymphocytes in PB/BM/LN
• Median age of 65• Male/female=2/1• Most asymptomatic• Transform to DLBCL (Richt
er syndrome), 3.5%• Rai classification (stage I, II, III, IV) or Binet cl
assification ( 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
Stage Clinical FeaturesMedian
Survival,Years
RAI System0: Low risk Lymphocytosis only in blood and marrow >10
I: Intermediate riskLymphocytosis + lymphadenopathy +splenomegaly ± hepatomegaly 7
II
III: High risk Lymphocytosis + anemia 1.5IV Lymphocytosis + thrombocytopenia
Binet System
AFewer than three areas of clinicallymphadenopathy; no anemia orthrombocytopenia
>10
BThree or more involved node areas; noanemia or thrombocytopenia 7
CHemoglobin 10 g/dL and/or platelets<100,000/l 2
Lymphoplasmacytic Lymphoma/Waldenström macroglobulinemia
• 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 l
ymphoma (MALToma) and follicular lymphoma
• Rearrangement of PAX-5 gene; t(9;14)• Indolent course• Aged, advanced stage, cytopen
ias, neuropathy, weight loss have poor prognosis
Plasma cell Myeloma
• Plasmacytosis• Osteolysis• M-protein• Nephropathy• Incurable
Plasma cell Myeloma-Natural History
Time (yr)
Tu
mo
r b
urd
en
MGUS
Diagnosis
TreatmentPlateau
Acceleration
0-2-5
TxM+PVAD
HDCT with AutoPBSCT
II3 7
IgG 40%IgA 25%Light-chain 20%Others 15%
Poor prognostic factor Monosomy 13 or 13q- Hypodiploidy
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
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
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
Non-Hodgkin Lymphoma
Diffuse Large B-cell Lymphoma
• Large B lymphoid cells • Broad age distribution• Male/female=1/1• Nodal (60%) vs. extranoda
l (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)
Burkitt Lymphoma
• 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
B-lymphoblastic lymphoma
Distinguish from ALL :PB invlvement (-) BM: < 25% blastExtramedullary tumor donimantTdT(+) , CD 10+, CD 34+ , CD19+ t(9.22) poor outcome
Follicular Lymphoma
• 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 lymp
homa is occassionally seen• Rearrangement of Ig with extensive s
omatic mutations and intraclonal diversity (GC cells)
• t(14;18)(most cases)(BCL-2 overexpression) & t(2;18)(less cases)
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
(MALT lymphoma)
• 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
*. Small lymphocytes, centrocytes, monocytoid, centroblasts, immunoblasts, plasmacytoid lymphocytes
Nodal Marginal Zone B-cell Lymphoma
• Expansion of marginal zone B (mostly monocytoid) cells without evidence of extranodal or splenic involvement
• Uncommon• Rare trisomy 3 and t(11;1
8) as seen in MALToma
• Indolent lymphoma• Poor response to chemoth
eray• Median OS, 5 years
Splenic Marginal Zone Lymphoma• 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 extra
nodal MZL, but not in SMZL• Indolent course, poor response
to chemotherapy• Splenctomy is considered
Hairy Cell Leukemia• Small B lymphoid cells with ov
al 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-chlorod
eoxyadenosine, deoxycoformycin, IFN, and splectomy are the choice of treatment
Mantle Cell Lymphoma
• 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
Mediastinal (thymic) Large B-cell Lymphoma
• 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
Intravascular Large B-cell Lymphoma
• 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
Primary Effusion Lymphoma
• 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-
• Germinal or Post-germinal center B cell (? Some from naïve B cells
• Poor prognosis(< 6m) despite the chemotherapy
• Antiviral treatment and proteosome inhibitors
CD5 CD23 FMC7
cyclinD1
CD10
CD103 CD11c
CD38 CD43 Remark
BL - - - + - - +/- Bcl-6+/CD45+/Ki-67 100%
FL - - - ++ - - - +/- Bcl-2+
MCL
++ - + ++ - - - - + Bcl-2+
CLL ++ ++ - - - - - -
HCL - - + +/- - ++ ++ -
SML - - - - - +/- - - CD21+/CD35+
Surface Marker Analysis of B-Lymphoid Malignancy
T cell lymphoma/leukemia
Precursor T lymphoblastic leukemia/lymphoma
• 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
T-cell Prolymphocytic Leukemia
• T-PLL, rare• Hepatosplenomegaly, lymphad
enopathy 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
Aggressive NK-cell Leukemia
• NK-cell proliferation• Rare, but more prevalent in Asians• Teenagers with male predominanc
e• PB/BM/LV/SN• Fever, constitutional symptoms, a l
eukemic 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
Adult T-cell Leukemia/Lymphoma
• 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 micro
abscess)• Acute, lymphomatous, chronic and
smoldering variants• P40 tax viral protein leads to trans
criptional 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(?)
Extranodal NK/T-cell Lymphoma, nasal type
• More prevalent in Asia, Mexico, Central and South America
• Adults and male predominant • Extranodal presentations• Nasal obstruction, epistaxis du
e 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, limite
d vs. disseminated
Mycosis fungoides
• Mature T-cell lymphoma presenting in skin
• Small to medium-sized cells with cerebriform nuclei
• Adults/elderly, male/female=2/1• Skin, extracutaneous dissemin
ation may occur• Initial patches, plaques on the t
runk
• Epidermotropic infiltration with Pautrier microabscess, and dermal infiltration
• CD2+/CD3+/CD5+/CD4+/CD8-• CD7-/HECA antigen+• Clinical stage, the most importa
nt prognostic factorStage characteristicsIa Skin, limited patches/plaquesIb Skin, disseminated lesionsIc Skin, tumor formationII LN enlargement, histology –III LN enlargement, histology +IV Visceral dissemination
Angioimmunoblastic T-cell Lymphoma(ALIT)
• PTCL, systemic involvement with proliferation of endothelial venules and follicular dendritic cells (CD21+ cells)
• Middle age, male/female=1:1• Generalized LAPs, hepatospl
enomegaly, 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
Peipheral T-cell Lymphoma, unspecified
• 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
Anaplastic Large Cell Lymphoma
• T-cell lymphoma (TCR rearrangement+)
• Large lymphocytes with abundant cytoplasm and pleomorphic (horse-shoe) nuclei
• ALK+ALCL, young age with male/female=6.5
• ALK-ALCL, elder age with male/female=0.9
• LN and extranodal sites of skin, bone, soft tissue, lung, liver and BM (more common in ALK+ALCL)
• CD30+/cytotoxic granule-associated proteins+/ALK protein+, by t(2;5)[ALK/NPM]
• CD2+/CD4+/CD3±/EMA+/CD15-• Common variant, lymphohistiocyti
c variant and small cell variant• DDX with HL and primary cutaneo
us CD30 positive T-cell lymphoproliferative disorders, c-ALCL & lymphomatoid papulosis
• IPI and ALK, as clinical prognostic factors (ALK+ vs. ALK-, 5 yr-SR=80% & 40% respectively