WBC related disease part II

1
WBC related disease part II
??????? ?????
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
A N T I G E N
BM
cIgMCD20
Plasma cell Myeloma
Follicular lymphoma t(1418)
CD23 Bcl-2
CD19 CD10 TdT Cu
Centrocyte
BM
IgM
Precursor B Lymphoblast
Naïve B
IgG/A CD20- CD38
CD20,CD5,sIgMD
CD10 Bcl-6
Burkitts lymphoma t(814)
IgMG
Centroblast
CD23-
Plasma cell
Mantle cell
Marginal Zone Monocytoid B cell
Mantle cell lymphoma t(1114)
Large B-cell lymphoma
Marginal Zone Lymphoma t(1118)
Germinal center
4
(No Transcript)
5
(No Transcript)
6
The Differentiation Stage of B T-cells
Determined the Type of Malignancy
Early Pre-B
Pre-B
Lympho- Plasmacytoid
Plasma cells
Immuno- blast
Mature-B
BM
Lymph nodes or lymphoid tissues
BM
Y
sIgM
sIgM/G/A
sIgM/G/A
Y
sIgM/D
Y
Y
Y
Y
Y
Y
Y
Y
HCR
HCR
KR/D
?R/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
7
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
8
WHO Hisological Classification of B-cell
Neoplasms

• 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

• 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

9
WHO Histological Classification of T-cell and
NK-cell Neoplasms

• 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

10
Cellular Origin of Lymphoma
NHL
HL
B-lymphocytes 8085
T-lymphocytes 1314
NK-cells 12
30
U.S. Europe
B-lymphocytes 5560
T-lymphocytes 4045
NK-cells ?
Taiwan
10
Immune deficiency Autoimmune disorder Infection
Autoimmune disorder Infection
?
Possible etiologies
?
11
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
• Burkitts 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

12

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

13
Staging of HL(Cotswold revision of the Ann Arbor
staging classification)
Stage Definition
I Involvement of a single lymph node or lymphoid structure (e.g., spleen, thymus, Waldeyers 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 diseasegt1/3 widening of the mediastinum at
T5-6, or maximun of nodal massgt10cm E,
involvement of a single extranodal site
14
A no symptoms B fever/sweats/weight loss X
bulky diseasegt1/3 widening of the mediastinum
at T5-6, or maximun of nodal massgt10cm 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)
15
International Prognostic Index for NHL
Five clinical risk factors  1. Age gt   60
years  2. Serum LDH elevated  3. Performance
status gt  2 (ECOG) or lt   70 (Karnofsky)  4.
Ann Arbor stage III or IV  5. gt1 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
16
(No Transcript)
17
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
18
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)

19
Common Clinical Characteristics of Hodgkin
Lymphoma

• Neck lymphadenopathy
• Young adult
• Hodgkin and Reed-Sternberg cells (HRS)
• Rich inflammatory backgroud

20
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma

• Monomorphic small and round B-lymphocytes in
  PB/BM/LN
• Median age of 65
• Male/female2/1
• 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 gt trisomy 12 gt 13 q gt
  14q

21
(No Transcript)
22
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 lymphoma (MALToma)
  and follicular lymphoma
• Rearrangement of
• PAX-5 gene t(914)
• Indolent course
• Aged, advanced stage, cytopenias, neuropathy,
  weight loss have poor prognosis

23
Plasma cell Myeloma

• Plasmacytosis
• Osteolysis
• M-protein
• Nephropathy
• Incurable

24
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 MP VAD
Treatment Plateau
HDCT with AutoPBSCT
MGUS
II
3
7
0
-2
-5
Time (yr)
25
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

26
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

27
in Mantle Cell Lymphoma

• Cancerous cells growing out of control in the
  lymph nodes
• Accounts for only 6 of the non-Hodgkins
  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

28
Non-Hodgkin Lymphoma
29
Diffuse Large B-cell Lymphoma

• Large B lymphoid cells
• Broad age distribution
• Male/female1/1
• 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)

30
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(814), t(28), t(822)
• CD5(-), CD10(), Pan B Ag()
• Highly aggressive, potentially curable after high
  dose C/T

31
B-lymphoblastic lymphoma

• Distinguish from ALL
• PB invlvement (-)
• BM lt 25 blast
• Extramedullary tumor donimant
• TdT() , CD 10, CD 34 , CD19
• t(9.22) ? poor outcome

32
Follicular Lymphoma

• 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(1418)(most cases)(BCL-2 overexpression)
  t(218)(less cases)

• Follicular centre B cells
• Median age of 59 years
• Male/female11.7
• Nodal disease, also in Spleen/PB/BM(40)
• Histology pattern follicular(gt75), follicular
  and diffuse(2575), minimally follicular(lt25)

33
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/female11.2

• Association of chronic inflammation, infections,
  (Helicobacter pylori, Borrelia burgdorferi)
  autoimmune diseases
• Antibiotics treatment, chemotherapy, surgical
  intervention

. Small lymphocytes, centrocytes, monocytoid,
centroblasts, immunoblasts, plasmacytoid
lymphocytes
34
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(1118) as seen in MALToma

• Indolent lymphoma
• Poor response to chemotheray
• Median OS, 5 years

35
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/female1/1
• Agegt50 years
• Involvement of spleen/BM/PB, rarely LN
• M-protein (30)

• Splenomegaly, autoimmune anemia or
  thrombocytopenia
• Deletion of 7q21-32
• Trisomy 3 and t(1118) in extranodal MZL, but not
  in SMZL
• Indolent course, poor response to chemotherapy
• Splenctomy is considered

36
Hairy Cell Leukemia

• 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/female5/1
• 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

37
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/female2/1
• LN/SN/BM/GI/
• Waldeyers ring/PB

• Rearrangement of Ig without somatic mutations
  (pre-GC cells)
• t(1114)(q13q32)
• IgH/CYCLIN D1
• Blastoid variant (classic vs. pleomorphic) with
  aggressive course
• Incurable with median OS, 35 years if no
  aggressive tx

38
Mediastinal (thymic) Large B-cell Lymphoma

• A subtype of DLBCL, arising from mediastinum of
  putative thymic B-cell origin
• 3040 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/TR/T
• Px, dependent on initial stage

39
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

40
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/csIg
  -

• Germinal or Post-germinal center B cell (? Some
  from naïve B cells
• Poor prognosis(lt 6m) despite the chemotherapy
• Antiviral treatment and proteosome inhibitors

41

Surface Marker Analysis of B-Lymphoid Malignancy
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
42
T cell lymphoma/leukemia
43
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/CD4CD8

• Rearrangement of TCRaandd(14q11),ß(7q35), and
  ?(7p15), with partners of MYC(8q24), TAL1(1p32),
  RBTN1(11p15), RBTN2(11p13), and HOX11(10q24)
• Rather unfavorable clinical outcome than B-ALL/LBL

44
T-cell Prolymphocytic Leukemia

• 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/CD48(60),CD48(25),
  CD4-8-(15)
• t(1414)(q11q32)
• Aggressive course
• Median OS lt 1 year
• CAMPATH-1 responsive

45
Aggressive NK-cell Leukemia

• 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 12 years

46
Adult T-cell Leukemia/Lymphoma

• CD2/CD3/CD5/CD25
• CD7-/CD4CD8-(rare, CD4-CD8)
• Clinical subtypes, performance status, age, Ca,
  LDH levels are prognostic factor
• In acute form, median OS12yrs
• Treatment choice INF AZT C/T(?)

• HTLV-1 related peripheral T-cell (flower cells)
  neoplasm
• Endemic in Japan
• Median age of 55 years with male/female1.5/1
• 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

47
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 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

48
Mycosis fungoides

• Epidermotropic infiltration with Pautrier
  microabscess, and dermal infiltration
• CD2/CD3/CD5/CD4/CD8-
• CD7-/HECA antigen
• Clinical stage, the most important prognostic
  factor

• Mature T-cell lymphoma presenting in skin
• Small to medium-sized cells with cerebriform
  nuclei
• Adults/elderly, male/female2/1
• Skin, extracutaneous dissemination may occur
• Initial patches, plaques on the trunk

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
49
Angioimmunoblastic T-cell Lymphoma(ALIT)

• PTCL, systemic involvement with proliferation of
  endothelial venules and follicular dendritic
  cells (CD21 cells)
• Middle age, male/female11
• 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 (gt75 cases)
• T-zone hyperplasia of LN, with a lot of reactive
  cells, included transformed immunoblastic B
  cells, and esp. FDCs
• CD2/CD3/CD5/CD4CD8/CD7-
• Aggressive course with a median OS lt 3 years

50
Peipheral T-cell Lymphoma, unspecified

• Half of the PTCL in Western countries
• Adults, male/female1/1
• LN/LV/Spleen/Skin
• Systemic symptoms and paraneoplastic features

• Lymphoepithelioid cell variant (Lennert lymphoma)
• CD2/CD3/CD5/CD4CD8-/CD30
• Complex cytogenetic changes, trisomy 3
• Poor prognosis, 5-yr SR2030
• Clinical stage and IPI, as prognostic factors

51
Anaplastic Large Cell Lymphoma

• T-cell lymphoma (TCR rearrangement)
• Large lymphocytes with abundant cytoplasm and
  pleomorphic (horse-shoe) nuclei
• ALKALCL, young age with male/female6.5
• ALK-ALCL, elder age with male/female0.9
• LN and extranodal sites of skin, bone, soft
  tissue, lung, liver and BM (more common in
  ALKALCL)

• CD30/cytotoxic granule-associated proteins/ALK
  protein, by t(25)ALK/NPM
• CD2/CD4/CD3/EMA/CD15-
• Common variant, lymphohistiocytic variant and
  small cell variant
• DDX with HL and primary cutaneous CD30 positive
  T-cell lymphoproliferative disorders, c-ALCL
  lymphomatoid papulosis
• IPI and ALK, as clinical prognostic factors (ALK
  vs. ALK-, 5 yr-SR80 40 respectively