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Lymphoproliferative disorders
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Mature Lymphoproliferative disorders (1)Dr. Douaa Mohammed Sayed
Overview
Concepts, classification,lymphomagenesis Epidemiology Clinical presentation Diagnosis Staging
Concept
neoplasms of lymphoid origin, typically causing lymphadenopathy
leukemia vs lymphoma lymphomas as clonal expansions of cells
at certain developmental stages
Stages of Maturation/DifferentiationL
ineagesLym
phoidM
yeloid
• cells are defined by lineage and stage of maturation/differentiation• regulated by signaling pathways and transcription factors• role of proliferation• cell “identity” may be determined using morphology, immunophenotyping and molecular/genetic studies
B-Lineage LymphopoiesisMorphology / Immunophenotyping / Molecular Studies
“Blasts” “Mature” Lymphocytes
B-cell development
stemcell
lymphoidprecursor
progenitor-B
pre-B
immatureB-cell
maturenaiveB-cell
germinalcenterB-cell
memoryB-cell
plasma cell
DLBCL,FL, BL, HL
LBL, ALL
CLLMCL
MM
MZLCLL
B-Lineage LymphopoiesisMorphology / Immunophenotyping / Molecular Studies
Markers are helpful in determining:
1. Lineage (ex. CD19)2. Maturation (ex. TdT, CD34, CD10)3. Both (ex. sIg)
B-Lineage LymphopoiesisMorphology / Immunophenotyping / Molecular Studies
• Status of immunglobulin genes (i.e., germline, rearranged, somatic mutations) has implications for both lineage and maturation.
Determining B-Cell Clonality by PCR
AML
ALL CLL
CML
Lymphomas
Lymphomas
The challenge of lymphoma classification
Clinically useful classification
Diseases that have distinct• clinical features• natural history• prognosis• treatment
Biologically rational classification
Diseases that have distinct• morphology• immunophenotype• genetic features• clinical features
Lymphoma classification(based on 2001 WHO)
B-cell neoplasms Precursor B-cell neoplasms Mature B-cell neoplasms B-cell proliferations of uncertain malignant potential
T-cell & NK-cell neoplasms Precursor T-cell neoplasms Mature T-cell and NK-cell neoplasms T-cell proliferation of uncertain malignant potential
Hodgkin lymphoma Classical Hodgkin lymphomas Nodular lymphocyte predominant Hodgkin lymphoma
A practical way to think of lymphomaCategory Survival of
untreated patients
Curability To treat or not to treat
Non-Hodgkin lymphoma
Indolent Years Generally not curable
Generally defer Rx if asymptomatic
Aggressive Months Curable in some
Treat
Very aggressive
Weeks Curable in some
Treat
Hodgkin lymphoma
All types Variable – months to years
Curable in most
Treat
Lymphomas
Morphology
Immunophenotype
Lymphomas
Molecular Features
Mechanisms of lymphomagenesis Genetic alterations Infection Antigen stimulation Immunosuppression
MOLECULAR PATHOGENESIS OFNON-HODGKIN’S LYMPHOMAS
Non-Hodgkin’s lymphomas (NHL) represent a heterogeneous group of diseases deriving from mature B cells 85% of cases) and, in a minority
of cases, from T cells. Among B-NHL, most histologic subtypes arise
from germinal center (GC) or post-GC B cells, since they have undergone hypermutation of the
immunoglobulin variable region (IgV) genes, a phenomenon restricted to GC B cells.
Activation of Proto-oncogenes by Chromosomal Translocation
In contrast with neoplasms of precursor lymphoid cells, chromosomal translocations
associated with mature B and T-cell malignancies do not generally lead to coding
fusions between two genes. They juxtapose the proto-oncogene to
heterologous regulatory sequences derived from the partner chromosome.
These sequences may derive from antigen receptor loci as well as from other loci that are
expressed at sustained levels in normal cells corresponding to the differentiation stage of the
lymphoma.
The two exceptions to the deregulation model of NHL translocations are
represented by the t(2;5) of T-cell anaplastic large cell lymphoma and the
t(11;18) of MALT lymphoma, which cause gene fusions coding for chimeric proteins.
Inactivation of tumor suppressor loci
Disruption of tumor suppressor loci in NHL occurs through mechanisms similar to those
associated with other human cancers and generally leads to biallelic inactivation, most frequently through deletion of one allele and
mutation the other. The tumor suppressor genes most frequently involved in the pathogenesis of
NHL are represented by p53, p16, and ATM (for ataxia telangiectasia mutated).
In addition, NHL frequently carry specific chromosomal deletions, which presumably represent sites of not yet identified tumor suppressor loci. The most frequent of these deletions involve the long arm of chromosomes 6 (6q) and 13 (13q).
Somatic hypermutation
Recent evidence suggests that important genetic changes associated with
lymphomagenesis may derive from an apparently aberrant activity of the somatic
hypermutation process that normally engenders Ig diversity in germinal center B
cells by mutating the IgV genes.