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NEOPLASTIC PROLIFERATION OF WBC 1
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Part I Neoplastic Proliferation Of Wbc

Oct 19, 2014

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Page 1: Part I Neoplastic Proliferation Of Wbc

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NEOPLASTIC PROLIFERATION OF

WBC

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LYMPHOID NEOPLASM MYELOID NEOPLASM - Hematopoietic stem

cells◦ MYELOID LINEAGE

1. ERYTHROID 2. GRANULOCYTIC

AML MYELODYSPLASTIC CHRONIC MYELOPROLIFERATIVE D/O

3. THROMBOCYTIC HISTIOCYTOSES

CATEGORIES:

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Acute Myelogenous◦ Immature progenitor cells accumulate in BM

Myelodysplastic Syndromes◦ Ineffective Hematopoiesis◦ Peripheral Cytopenias

Chronic Myeloproliferative D/O◦ Increased production◦ 1 or more terminally differentiated myeloid

elements GRANULOCYTES

◦ Leads to elevated peripheral blood counts

Granulocytic Lineage

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CHROMOSOMAL TRANSLOCATION AND ONCOGENES

• Lymphoid Neoplasms• Oncogenic rearrangement• Mutation in oncogenes r/t inherent

genomic instability of germinal B cells• Myeloid Neoplasms

• Chromosmal translocation• Unknown mechanism

Pathogenetic factors

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Mutated genes Produce Negative protein◦ Interfere with its normal function/ or Inapropriate increase

in some normal activity ( MALTomas ) Translocation of either MALT1 or BCL10 protein Upregulation

of NF-kB Normally Bind to form complex regulate NF-kB NF-kB has important pro-survival function in normal lymphocytes

Oncoprotein created by genomic abberations◦ Often Block normal maturation Affect rapidly

proliferating cells◦ Acute Leukemias

Proto-Oncogenes◦ Often activated in lymphocytes by errors that occur during

attempted antibody diversification

Chromosomal Translocation & Other Acquired Mutations

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Inherent Genetic Factors

• Promote genomic instability• Down syndrome• Fanconi anemia

Pathogenetic factors

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Viruses

• HTLV-1• Adult T cell Leukemia/ Lymphoma

• EBV• Burkitts, Hodgkins• Diminsihed T cell dependent Immune

surveillance• KSHV/HHV-

• Kaposi sarcoma herpes virus/• Human herpes Virus 8

Pathogenetic factors

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Chronic Immune Stimulation

H. pylori- Gastric lymphoma

Gluten enteropathy – Intestinal lymphoma

T cell dysregulation Systemic hyperplasia of germinal center B cells • HIV B cell

Lymphoma• Arise w/in virtually

any organ

Diminsihed T cell dependent Immune surveillance• EBV

Pathogenetic factors

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Iatrogenic Factors

Mutagenic effects on Progenitor cells• Radiotherapy• Chemotherapy

Pathogenetic factors

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Incidence of AML increased 1.3 to 2 fold in smokers

Exposure to carcinogens like benzene in tobacco smoke

Smoking

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LYMPHOID NEOPLASMS

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CLASSIFICATION:

1. Lymphocytic Leukemia2. Lymphoma3. Plasma cell Neoplasm

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Lymphoid neoplasmWidespread Bone Marrow Involvement

Usually (+) Large Numbers of Tumor cells in Peripheral smear

Lymphocytic leukemia

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Proliferations arising as Discrete tissue masses

2 Types◦1. Non-Hodgkins Lmphoma◦2. Hodgkins Lymhoma

Many types present with Leukemia◦Term used – Tissue distribution of the

disease at time of clinical presentation

lymphoma

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Most commonly arise in Bone Marrow

Rarely present as LeukemiaR/T Secretion of Antibodies by tumor cells

Plasma cell Neoplasm

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Vast majority are B cell in origin Markers recognized by Antibodies help in characterization into 5 categories

Often disrupt normal architecture & function of Immune system◦Susceptibility to infection◦Autoimmune

FEATURES- Lymphoid Neoplasm

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Inherited or acquired Immunedeficiency High risk certain lymphoid neoplasm◦Particularly caused by oncogenic virus eg. EBV

FEATURES- Lymphoid Neoplasm

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Tend to home to a particular tissue sites◦Follicular Lymphoma – Germinal

center◦T-cell Lymphomas – Skin

Some recirculate through the lymphatics & peripheral blood Distant sites◦Except Hodgkins, Marginal zone

lymphoma ( MALToma )

FEATURES- Lymphoid Neoplasm

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Determined by Anatomic distribuation of disease◦2/3 NHL and 100% of Hodgkin

Lymphomas Enlarged Nontender LN Often > 2 cm

◦Remaining 1/3 NHL Symptoms r/t to involvement of Extranodal

sites Skin, Stomach, Brain

Clinical PresentationLymphoma

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Abrupt stormy onset◦Present w/in days to few weeks

S/S related to Suppression of normal Hematopoiesis by tumor cells in BM

Characteristic is Infiltrate in Spleen & Liver

LYMPHOCYTIC LEUKEMIA

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Involve the skeleton◦Local bone destruction◦Pain◦Pathologic Fractures

Addendum◦Secretion of whole Ab or Ig fragments

PLASMA CELL NEOPLASM

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Precursor B cell Neoplasm◦Immature B cells

Peripheral B cell Neoplasms◦Mature B cells

Percursor T-cell Neoplasm◦Immature T cells

Peripheral T-cell & NK cell Neoplasm◦Mature T cell & NK cells

Hodgkin Lymphoma

WHO 5 CATEGORIES

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Acute Lymphoblastic Leukemia/Lymphoma

Precursor B and T –Cell Neoplasms

- Neoplasm of Immature B cells

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Group of Neoplasm composed of Immature pre-B or Pre-T LYMPHOBLASTS

Most common cancer of ChildrenSlightly higher in boys2 Types:

◦ 1. Pre-B cell ◦ 2. Pre-T cell◦Both tumors types are morphologically indistinguishable

Features :

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85% are B-ALLs◦Manifest as Childhood Acute Leukemia◦Peak age is 3 y/o◦Extensive BM involvement◦Variable Peripheral involvement◦Uncommonly present as Lymphoma

Less common is T-ALLs◦Adolescent males◦As Thymic Lymphoma◦Many evolve to Leukemia

Features :

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B-ALL◦ Leukemic Presentation◦ Marrow Hyperplasia and packed with

Lymphoblast T-ALL

◦ Mediastinal thymic mass ◦ Often with LNadenopathy & Splenomegaly

Morphology

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Lymphoblast in PBS◦Definitve Dx based on Lymphocyte –specific markers with Antibodies

◦Histochemical stain Negative for myeloperoxidase Often (+) PAS in cytoplasmic aggregates

◦Immunophenotype (+) TdT in > 95% of cases

DNA polymerase Expressed only in pre-B and pre-T lymphoblast

Morphology :

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Acute Lymphoblastic Leukemia

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B-ALL lymphoblast (+)◦CD19, CD10, CD19, CD20

T-ALL lymphoblast (+)◦CD1, CD2, CD5, CD7

Arrest in normal Maturation of Lymphoblast◦Dysregulation in epxression and function

of transcription factors

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About 90% ALL have numerical or structural chromosomal changes◦ Most commonly – Hyperploidy

> 50 chromosomes◦ Hypoploidy◦ Translocation

Hyperploidy & Hypoploidy are seen only in B-ALL

B & T ALL are associated wuth completely different sets of translocation

Molecular Pathogenesis

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70% of T-ALL ◦ Have gain-of-function mutations in NOTCH1◦ NOTCH1 is essential for T-cell development

High Fraction of B-ALL◦ Have loss-of-function mutations in genes for B cell

developmentNET EFFECT:

1. Disturb differentiation of Lymphoid precursor2. Promote Maturation arrest

Single mutations are not sufficient to produce ALL Must Acquire additional mutation before ALL develop

Molecular Pathogenesis

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Abrupt stormy onset Present w/in days to few weeks Symptoms r/t bone marrow suppression◦ Anemia , Infection, Bleeding episodes

Clinical Features :

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Mass Effects◦ Bone pain & tenderness ◦ Generalized Lymphadenopathy, Splenomegaly,

Hepatomegaly ◦ T-ALL

Complications R/T complression of large vessels and Airways in mediastinum

Both may have CNS manifestation◦ Due to meningeal spread◦ Headache, Vomiting, Nerve palsies

Clinical Features :

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Aggressive ChemoTx often w/ prophylactic CNS treatment◦> 95% of children achieve complete remission

◦75-85% of choldren are CuredStill the leading cause of cancer death in children

Treatment & Prognosis :

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< 2y/o Presentation in adolescence or childhood

Peripheral blast count > 100,000 Presence of Ph’ chromosome

◦T(9;22)◦Commonly seen in adult patients

ALLOGENIC BM TRANSPLANT – POOR PROGNOSTIC CATEGORIES

Unfavorable Prognostic Factors

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Age 2-10 y/oLow WBC countEarly pre-B phenotypeHyperploidy or t(12;21)

Favorable Prognostic Factor

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Peripheral B cell Neoplasm- Neoplasm of Mature B cells

1. Chronic Lymphocytic Leukemia & Small Lymphocytic Lymphoma

2. Follicular Lymphoma3. Diffuse Large Cell Lymphoma4. Extranodal marginal zone Lymphoma5. Burkitts Lymphoma

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CHRONIC LYMPHOCYTIC LEUKEMIA –CLLand

SMALL LYMPHOCYTIC LYMPHOMA- SLL

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Features•Similar - Morphological, Phenotype, Genotype

•Differ only in degree of peripheral blood Lymphocytosis

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Features•CLL – Chronic Lymphocytic Leukemia

▫ Most common leukemia of Adults in Western countries Median age 60 y/o 2:1 male preponderance

▫Diagnostic Criteria Absolute Lymphocytosis > 4000 per mm3

▫PERIPHERAL BLOOD WBC counts is High Increased numbers of Small Lymphocytes Smudge cell

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Chronic Lymphocytic Leukemia

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Features• SLL – Small Lymphocytic Lymphoma.▫Represent 4% of Non-Hodgkin Lymphoma▫Total WBC count is Variable▫If w/ Bone Marrow Involvement can

present as Leukopenia▫LYMPH NODE

Diffusely Effaced , Predominant Small Lymphocytes

Variable large Prolymphocytes CREATE PROLIFERATION CENTERS

▫PATHOGNOMONIC FOR CLL/SLL

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Small Cell Lymphoma

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Immunophenotype/ Molecular Genetics•CD5 – present in tumor cells

▫T-cell marker ▫Expressed by small subset of normal B

lymphos•Chromosomal translocation is rare•Most are Deletions

▫13q14▫11q▫17p

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Clinical Features•Mostly over 50 y/o•Male > Female 2:1•Often Asymptomatic•Nonspecific symptoms when manifest

•BONE MARROW INVOLVEMENT▫All cases of CLL▫Most cases of SLL

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Clinical Features

•50-60% show▫Generalized Lymphadenopathy▫Hepatosplenomegaly

•VARIABLE INVOLVEMENT OF SPLEEN & HEPATIC PORTAL TRATS

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Clinical Features

•Disrupts Immune function▫Hypogammaglobulinemia – Susceptible to INFXN

▫Autoimmune Auto-Antibodies produced by non-neoplastic B cells

▫ 10-15% develop Hemolytic anemia /Thrombocytopenia

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Prognosis

•Extremely Variable▫Depend mostly on Stage

•Overall Median is 4-6 years•Minimal Tumor burden 10 years

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Poor Prognostic Factors

•Presence of Deletions 11q & 17p▫Usually higher stage

•Transformation to higher grades▫Prolymphocytic 15%-30%

Worsening cytopenias Increasing Splenomegaly

▫Diffuse Large cell 5%-10% Rapidly enlarging mass w/in LN or spleen

Richter syndrome▫Survival < 1 year