Epidemiology of NHL
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Transcript Epidemiology of NHL
Epidemiology of NHL
4%
of all cancers
4% of all deaths
8.5 cases / 100.000 / year <65
69 cases / 100.000 / year >65
M:F 1.8 <65 1.3 > 65
higher incidence in Western than
developing countries
incidence increased 3 fold 1975-95
NHL : etiologic factors
Immunodeficiency
: primary and acquired
(HIV, post-tansplant)
Virus: HTLV-1, EBV
Helicobacter Pylori
Autoimmune disorders
Occupational exposures (pesticides,
solvents, dyes)
Other (weak association): diet (milk, meat),
blood transfusions, familial
Ann Arbor Staging
I:
a single lymphatic region or extranodal site
II: two or more regions on the same side of
diaphragm or one extranodal site and one or
more lymphatic
III: Involvement on both sides of diaphragm
IV: disseminated to liver, lung, BM, pleura,
bone, skin
Diagnostic procedures
History
(B symptoms)
physical examinations (lymph nodes,
hepatosplenomegaly, Waldeyers ring etc)
Lab.: complete blood count, LDH, b2microglobulin, renal and liver function
Chest X-ray, abdominopelvic CT scan
bilateral BM biopsies and PB smear
Hematopathology Lab.
Processing
and diagnosis of bone marrow,
blood, lymph nodes, tonsils, thymus, spleen
and other tissues with suspect lymphoma
Methods:
routine
histopathology
immunohistochemistry on frozen and paraffin
sections
flow cytometry
DNA analysis
molecular biology
Routine histopathology
Fixatives:
B5
and formaline
Stainings
Htx-eosine
Giemza
PAS
Gordon-Sweet
frozen
B5 form.
imprints: DNA
flow
LYMPHOMA
CLASSIFICATIONS
Kiel
classification 1974, rev. 1992
Lukes and Collins classification 1974
Working Formulation 1984
REAL (Revised European-American
Classification) Harris et al.
Blood, 1994, 84, 1361-1392
B-cell lymphomas
Postulated
stem
cell
AUL
normal counterparts:
BM B cell
precursor
B-precursor
ALL/NHL
null
common
pre-B
Peripheral B-cells
Lymph
nodes
Peripheral
blood
Mucosa associated
lymphatic tissue
B-cell lymphomas
Postulated
normal counterparts:
• Peripheral B-cells
Marginal zone
Lymph
small
lymphocyte node
Mz
Mt
Mantle zone
FCC
CB
B-cell
Burkitt?
CC
HCL???
Ig producing
Lpl/IC
PC
recirculating
B-cell
GC
Proliferating B-cell
Large cell NHL
CLL
REAL Classification
B
cell neoplasms
I.
B-precursor neoplasms
lymphoblastic leukemia/lymphoma
II.
Peripheral B-cell neoplasms
REAL Classification
II.
Peripheral B-cell neoplasms
1. B-CLL
2.Lymphoplasmocytoid lymphoma immunocytoma
3.Mantle cell lymphoma
4.Hairy cell leukemia
5.Plasmacytoma/myeloma
NHL : Flow cytometry
Morphology: Lymphocytic lymphoma
Immunophenotype: CD19+, kappa+, CD5+,
CD23+, CD20-, mCD22-, CD10-
NHL : Flow cytometry
Immunocytoma
Monoclonal
k, CD19+, CD20+, CD22+, CD5-,
CD10-, CD2360% B cells,
80% B cells CD5-
Monocl. kappa
NHL : Flow cytometry
Morphology:
Mantle cell lymphoma
CD19+
CD5 dim
CD5 dim
CD23-
NHL : Flow cytometry
HAIRY CELL LEUKEMIA
CD19+
cells have characteristic scatter, CD5-,
CD10- (some cases +)
CD19PE
CD5FITC
NHL : Flow cytometry
HAIRY CELL LEUKEMIA
CD19+
cells are Bly7+, CD11c+, CD25+
NHL : Flow cytometry
Myeloma
- plasmocytoma:
CD19-, CD20-, CD22-, CD23-, CD5-,
CD10CD38 bright,
CD45neg
R4
CD56+
REAL Classification
II.
Peripheral B-cell neoplasms
6. Follicle Center Cell (FCC)
grades:
I (small cell), II (mixed small and large cell), III
(large cell)
7. Marginal zone B-cell
extranodal (MALT +/- monocytoid cells)
nodal (+/- monocytoid cells)
splenic marginal zone (+/- villous lymphocytes)
NHL : Flow cytometry
Morphologic
diagnosis :
Low grade Marginal zone NHL
Triple staining
FITC/ PE/ CD20PerCP
64% B cells
R1
Monocl.
NHL : Flow cytometry
Morphologic
diagnosis :
Low grade Marginal zone NHL
Tripple stainings CD23 F/CD5 PE/ CD19TRI and
CD22 F/CD10PE/CD19 TRI
Most B-cells
express CD22 dim
and are CD10-
14% B cells CD23+
4%B cells CD23+/5+
7% of B cells CD5+
Localizations of MALT lymphomas
conjunctiva
inc. orbit
salivary glands
Waldeyer's ring
larynx
thyroid gland
breast
lung
GI tract
urogenital tract
NHL : Flow cytometry
MALT
lymphoma, gastric mucosa px
B cells were CD20+, CD22+, CD5-, CD10-,
CD23
60%
B cells
NHL : Flow cytometry
Morphology:
FCC type II
Partial involvement (confirmed by bcl-2 IH)
45% B-cells
R5
ratio:
0,5
NHL : Flow cytometry
Morphology:
FCC II (CB/CC foll&diff)
A CD19 dim population was present
NHL : Flow cytometry
Morphology:
The
for
FCC II (CB/CC foll&diff)
medium/large sized cell population is monoclonal
NHL : Flow cytometry
Morphology:
The
FCC II (CB/CC foll & diff)
medium/large sized cell population is CD10+ and CD22
dim, CD5-, CD23-
REAL Classification
II.
Peripheral B-cell neoplasms
8. Diffuse Large B-Cell
include
various subtypes
one defined: mediastinal (thymic) B-NHL
9.
Burkitt´s lymphoma
10. High-grade Burkitt-like
NHL : Flow cytometry
Large
cell B-NHL (CB polym. diff.)
Staining CD5F/CD19PE/CD3PerCP
CD20-, mCD22-, CD23-, CD10 some cells positive for
in large cell-gate
32% of cells
in large-cell gate
83% CD19+
NHL : Flow cytometry
Lymphoblastic
lymphoma Burkitt-like
78% B cells
CD19+. CD20dim,
m CD22 neg
L3
Scatter
R1
NHL : Flow cytometry
Lymphoblastic
lymphoma Burkitt-like
CD19+, CD5-
CD10+
CD22 neg
T-cell lymphomas
Postulated
BM stem
cell
normal counterparts:
THYMUS
m3-/4-/8AUL
T-cell m3-/4+/8+
precursors
T ALL 4+ or 8+
cyt.CD3+/TdT+
Peripheral T-cells
skin
MF, SS
Mucosa, bowel
Intest. T cell NHL
Lymph node
Peripheral
T NHL
ANLC
sinus
REAL Classification
T cell neoplasms
I. Precursor T-cell
lymphoblastic
leukemia/lymphoma
II. Peripheral T cell and NK-cell
neoplasms
REAL Classification
II.
Peripheral T cell and NK-cell
neoplasms
1.
T CLL
2. Large granular lymphocyte (LGL)
leukemia
T-cell type
NK-cell type
3.Mycosis fungoides/Sezary syndrome
REAL Classification
II.
Peripheral T cell and NK-cell
neoplasms
4. Peripheral T cell lymphoma
cytologic
categories: medium sized, mixed medium
and large cell, large cell-lymphoepithelioid cell
5. Angioimmunoblastic
T-cell
lymphoma AILD
6. Angiocentric lymphoma
REAL Classification
II.
Peripheral T cell and NK-cell
neoplasms
7. Intestinal T cell lymphoma
(+/-
enteropathy associated)
8. Adult
T cell lymphoma/leukemia
9.Anaplastic large cell lymphoma
CD30+, T-and null cell types
NHL : Flow cytometry
Peripheral
T cell NHL
mCD3-, cytCD3+, CD4+, CD8-,
CD7+, CD2+,CD5+, HLA-DR neg.
84% T cells
mCD3-/CD4+
NHL : Flow cytometry
Peripheral
80%
T cell NHL
of CD4+ cells were CD45RA, Leu8dim+
gated on
CD4/SSC
*TRC V g 1.3 rearrangement
Dermatopatisk lymphadenopathy
CD4/CD8
ratio 15:1
All T cells positive for mCD3, CD5, CD2, CD7
Activation of CD4 cells
Dermatopatisk lymphadenopathy
CD4
positive cells not clonal (no TCR
rearangement)
Cd45RA:CD45R0 0,35
predominance of CD62L+
or
Immunohistochemistry
Frozen
sections:
skin biopsies, bone marrow biopsies
APAAP method
Paraffin sections
lymph nodes and other tumors
Immunoperoxidase method
Ventana
Immunohistochemistry
Panel
of antibodies
B
T
Other
CD20
CD3
MIB-1
CD79
UCHL-1
CD45
k/l
CD43
CD68
LN1
CD4/CD8 CD30,CD15
FLow cytometry
Multiparameter analysis
Triple
immunofluorescence:
CD14/GPA/CD45
B
T
lambda/kappa/CD20 CD4/CD8/CD3
CD22/CD10/CD20
CD7/CD2/HLA-DR
CD23/CD5/CD19
CD16/CD56/CD3
Flow cytometry
Other
panels
T cells
Hairy cell leukemia
CD25/CD56/CD3
CD45RA/CD45RO/CD4
CD45RA/CD45RO/CD8
CD62L/CD4/CD8
CD103/CD19/CD20
CD11c/CD19/CD20
CD25/CD19/CD20
Other methods
DNA index
Feulgen
staining on imprints
PI staining by flowcytometry
Molecular methods
TCR rearrangement
Heavy chain rearrangement
PCR for translocations
Chromosomal abnormalities in
some NHL entities
CLL B
tri 12, abn. 13q
mantle cell t(11;14) bcl-1
FCC
t(14;18) bcl-2
Burkitt t(8;14),t(8;22),t(2;8) C-myc
CLL T
inv.14(q11;32), tri.8
low grade T tri.3, 5 or +X
large cell anaplastic t(2;5)
Future clinical trials
Aggressive
lymphomas
Dose
intensity and dose size
High dose sequential therapy
Indolent
nucleoside
lymphomas
analogs (CDA)
immunotherapy
monoclonal antibodies
antisense nucleotides
Bone marrow ref.
Tumors
of the Bone Marrow
Brunning R.D., McKenna R.W.
Armed Forces Institute of Pathology, Fasc. 9
Bethesda, MD, 1994
Pathology
of Bone Marrow
Naeim F.
Igakuy-Shoin, New york, Tokyo 1992
Lymphomas ref.
Atlas of Lymphoid Hyperplasia and
Ferry JA., Haris NL.
WB. SAuders Co, Philadelphia, London etc. 1997
Lymphoma
Extranodal Lymphomas
Isaacson PG., Norton AJ.
Churchill Livingstone, Edinburgh, London etc., 1994
Thymus,
Lymph Nodes, Spleen and Lymphatics
Henry K., Symmers W.St C.
Churchill Livingstone, Edinburgh, London etc., 1992