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.