NEOPLASTIC PROLIFERATION OF WBC 1
Oct 19, 2014
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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