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

CD2CD5CD3

CD1CD4/8

Precursor T-cell leukemia/lymphoma Peripheral T-cell neoplasms

Classification of Lymphoma1982• Working formulation

– Low grade (LG)– Intermediate grade (IG)– High grade (HG)

1994• Revised European-American

Lymphoma (REAL)– Emphasize Immunopheno

type

2001WHO 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 DefinitionI 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 EA, 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 (Richte

r 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)

Tumor

burden

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 curabl

e 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 (fl

ower 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 presen

ting in skin• Small to medium-sized cells wit

h 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 par

aneoplastic 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