Wbc Neoplasms Review - Pathology

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Lasanthi Aryasinghe

• Abrupt stormy onset (days-wks) • Depression of BM causes:

- Fatigue (due to anemia)

•Immature, precursor

B or T lymphoctyes Lymphoblasts

• 85% are pre-B-cell

pre-B & pre-T ALLs done by Immunophenotyping

- Bleeding (due to  platelets)

• 80% of childhood

• Generalized lymphadenopathy

leukaemias • Less common:

• FAB Classification:

- L1ALL, L2ALL, L3ALL Blast size, cytoplasm characteristics & nuclear:cytoplasmic ratio

- Infection (absent mature WBC)

childhood acute leukaemia (4 yrs)

• Distinction between

Acute Lymphoblastic Leukaemia/ Lymphoma (ALL)

Pre-T-cell “lymphomas” in adolescents w/ thymic involvement

Lymphoblasts (LN):

• Bone pain (marrow expansion)

• Splenomegaly & hepatomegaly

due to neoplastic infiltration • Pre-T ALL thymus involved 

compression of mediastinal structures

• Little cytoplasm

Cytochemistry: • PAS stain block +ve

 B- ALL • Acid Phosphatase

stain +ve  T-ALL • MPO –ve in ALL

(Agranular) • Large nuclei • Delicate, finely stippled

chromatin • Absent / inconspicuous

nucleoli • Nuclear membrane

shows subdivisions “lobulated” appearance

• Testicular involvement (ALL) • CNS (headache, vomiting, nerve

• High mitosis rate

palsies) due to meningeal spread, more common in ALL than AML

Immunostaining for Terminal deoxynucleotidyltransferase (TdT) (+ve 95% of ALL) Pre-B-ALL: CD: 19, 22, 10 Pre-T-ALL: CD: 1, 2, D5, 7 Early pre-T cells: -ve for CD: 3, 4, 8

90% of ALLs have numerical or structural changes: • Hyperploidy

Aggressive chemotherapy + prophylactic treatment of CNS  90% Remission

• Polyploidy • t(12;21)

Poor Prognosis:

• t(9;22):

• Age <2yrs

Philadelphia chromosome • t(4;11) • Translocations of

(11q23)- MLL gene rearrangements

• Adolescence or adulthood • PB blast counts >100, 000

(high tumor burden) • Philadelphia chromosome

• “Starry Sky”:

interspersed benign macrophages that have ingested debris of dying neoplastic cells Peripheral Blood Film:

• Peripheral B-cell

Neoplasm / Lymphoma

•Leucocytosis

• SLL 4% of all NHLs

• Absolute

• Morphologically,

lymphocytosis: >5×109/L

phenotypically & genotypically indistinguishable

• Symmetrical superficial LN

enlargement: discrete and nontender

• CLL & SLL differ

Chronic Lymphocytic Leukaemia (CLL) & Small Lymphocytic Lymphoma (SLL)

only in the degree of peripheral blood lymphocytosis

• Splenomegaly + hepatomegaly • Features of : Anaemia, • Older subjects,

Staging of CLL: • Rai Classification

rare <40yrs • <<Males; 2:1

Thrombocytopaenia, Immune deficiency (association w/ Herpes zoster) • Hypogammaglobulinemia

(normal Ig)   susceptibility to infections

- Lymphocytosis - Lympadenopathy - Enlarged liver/ spleen - Anemia (Hb<10mg/dl) - Thrombocytopenia (<100 x 109/L)

• Auto-antibodies against RBCs

or platelets (Autoimmune haemolytic anaemia / thrombocytopaenia can occur)

• Small, round

lymphocytes with scanty cytoplasm

- Stages A, B, C - Organ areas 0-5 - Anemia - Thrombocytopenia

• Architecture: effaced

• Smudge/ Smear cells

fragile lymphocytes disrupted during smearing • Normochromic

Normocytic anaemia - Autoimmune haemolytic anaemia : Round spherocytic RBCs - BM failure - Hypersplenism Serum Protein Electrophoresis: Hypogammaglobulina emia

• Binet et al:

Lymph Node Biopsy:

• Predominant

population: small lymphocytes 6-12 µm containing: - Round, slightly irregular nuclei - Condensed chromatin - Scanty cytoplasm • Variable numbers of

Tumor cells express: CD: 5, 20, 23 & low level expression of Surface Ig (IgM &D) Immunoperoxidase staining shows tumor cells are monoclonal due to expression of one form of light chain either κ or λ

large prolymphocytes (high mitotic rate) gathered together forming loose agregates “proliferation centers” PATHOGNOMIC of CLL/SLL

Chromosomal translocations are rare Deletions of : •13q14 •11q23 •17p •Triosomy 12q

Ig genes of some CLL/SLL are somatically hypermutated

Variable and dependent on clinical stage Poor Prognosis: • Deletions of 11q & 17p

CLL/SLL can transform to more aggressive lymphoid neoplasms: • Prolymphocytic transformation (B CLL/ PLL) • Large B-cell lymphoma

(Richter syndrome)

BM Biopsy/Aspirate: Lymphocyte infiltrate of normal elements Tumor cells infiltrate spleen and hepatic portal tracts. Pheripheral Blood: Lymphocytosis (<20,000 per mm3) seen in only 10% cases BM Involved in 85% of cases: paratrabecular lymphoid aggregates • Painless, generalized

• Peripheral B-cell

Follicular Lymphoma

Lymphoma • Accounts for 45% of

adult lymphomas

• Middle age • Males = Females

lymphadenopathy

Spleen

• Involvement of extranodal sites

• Incurable, however it has

Tumor cells express: CD: 19, 20, 10 and Surface Ig Neoplastic cells: • Resemble normal

germinal center B cells • Predominately nodular

or nodular and diffuse growth pattern

as GIT, CNS or testis is relatively uncommon.

• Two principal cell types:

Prominent nodules represent white pulp follicles expanded by follicular lymphoma cells Hepatic Portal triads also involved

- Majority: small cells w/ irregular cleaved nucleus & scanty cytoplasm centrocytes - Larger cells with open nuclear chromatin, several nucleoli & modest amount of cytoplasm - centroblasts

Unlike CLL/SLL & mantle lymphoma FL does not express CD5 but expresses BCL2 protein in >90% of cases Almost all tumors express BCL6 (transcriptional repressor- regulates germinal center B cell development)

an indolent waxing & t(14;18): waning course Juxtaposition of IgH • Median survival: 7 to 9 yrs locus on chromosome 14 & • Not improved by BCL2 locus on aggressive therapy, hence, chromosome 18 clinical approach is to (overexpression of palliate patients with low BCL2) dose chemotherapy or radiation when they Uncommonly, may develop symptoms lack t(14;18) & instead have rearrangement of • Histologic transformation in 30%-50% of cases to: BCL6 gene on chromosome 3q27 - Diffuse Large B-cell Lymphoma - Burkitts lymphoma (Rare)

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Lasanthi Aryasinghe

• 30%:

Unlike low grade lymphomas, pts w/ present:

• Peripheral/Mature

B-cell Lymphoma group of tumors, Diffuse large B• 20% of all NHL cell lymphoma • 60%-70% of (DLBCL) aggressive lymphoid neoplasms

•Relatively large cell size

(4-5 times x diameter of a small lymphocyte) Diffuse pattern of growth

• Rapidly enlarging often

• Heterogeneous • Slightly <Male • 60 yrs

• “High grade”

symptomatic, mass at a single nodal or extranodal site (e.g. skin & GIT) • Can arise at any site; Waldeyer

ring, oropharngeal lymphoid tissues (tonsils & adenoids) commonly involved • 1° or 2° involvement of liver &

lymphoma

spleen in the form of destructive masses

Dysregulation of BCL6 (regulator for formation of germinal center)

Neoplastic cells:

• Nuclei are round or

Spleen Presence of isolated large mass is typical (while indolent B-cell lymphomas produce multifocal expansion of white pulp)

oval, appear vesicular due to chromatin margination at nuclear membrane can sometimes be large multilobated or cleaved

Tumor cells express: CD: 19, 20 & Surface Ig Variable expression of germinal center markers CD10 & BCL6 All are TdT negative

• 1-3 Prominent Nucleoli

• 10%: t(14;18) and

cREL amplification in a subset

Oncogenic viruses:

Aggressive fatal tumor- if untreated Intensive chemotherapy in 60-80%  Remission

HIV/EBV: Immunodeficiency associated large Bcell lymphoma HIV or KSHV/HHV8 Body cavity large cell lymphoma

• Cytoplasm moderately

abundant: pale or basophilic • Anaplastic tumours may

contain multinucleated cells with large inclusions like nucleoli

Most manifest at extranodal sites Largely in children and young adults: • Peripheral B-cell

Lymphoma • Lymphomatous

Burkitt’s Lymphoma

correlate of Acute Lymphoblastic Leukaemia (ALL) • 30% of childhood

African (endemic) • <<Males 5-10 yrs • EBV 95% of cases Sporadic • <<Males • EBV 20% of cases

• Endemic tumor: presents as a

mass (lympadenopathy) in the mandible with involvement of abdominal viscera (particularly the kidneys, ovaries, and adrenal glands) • Sporadic tumor: present as

abdominal mass involving ilioceacum & peritoneum

• Containing round to

oval nuclei with coarse chromatin •Lack of nuclear variation

in shape & size gives a monotonous apearance

• CD: 19, 20, 10 • Surface IgM • BCL6

• Moderate amt of faintly

• Monotypic κ or λ

• High mitotic index &

Involvement of BM & peripheral blood is uncommon.

Mature B-cells of the tumor express:

• Several nucleoli

basophilic cytoplasm

NHLs Subset of aggressive lymphoma • Individuals w/ HIV

Lymph Node Biopsy: Involved tissue effaced by diffuse infiltrate (sheets) of intermediatesized lymphoid (1025µm) cells:

apoptotic tumor cell death is typical  numerous pale Tingible body macrophages with ingested nuclear debris “Starry sky pattern”

In virtually every case the C-MYC oncogene on chromosome 8 is translocated to an Ig gene: • t (14;8) • t (2;8) • t (8;22)

light chain • Essentially all

endemic tumors have latent EBV

BM aspirated cells: • Slightly clumped chromatin • 2-5 distinct nucleoli • Blue cytoplasm with

multiple, clear vacuoles

• Predominant tumor

cell resemble normal Marginal Zone B-cell (mature) • Heterogeneous

Marginal zone Lymphomas/ Tumors of MALT: Maltoma

group of tumors that arise within LN, spleen or extranodal tissue • Association with

inflammation suggests that these neoplasms lie b/w reactive lymphoid hyperplasia and fullblown-B-cell lymphoma

Tumors are localized, extranodal: Gastric MALT lymphoma is most common form; preceded by Helicobacter Pylori gastritis

• Arise within tissue with pre-

exisiting chronic inflammatory disorders of autoimmune or infectious etiology • Remain localized for long, may

spread late in their course • May regress if the inciting agent

(e.g. H. pylori) is eradicated

Splenic Marginal Zone Lymphoma (Benign): Massive Splenomegaly w/circulating monoclonal B-cells w/ a villous appearance

Tumors acquire chromosome aberrations t(11;18) or t (1;14) @ extranodal sites  makes tumor nonresponsive to antibiotic therapy Translocations  tumor progression independent of original extrinsic stimuli e.g. H.pylori

• Very agressive but

responds well to short term, high dose chemo. • Most children and young

adults can be cured, but the outcome is more guarded in older adults

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Lasanthi Aryasinghe

BM showing abnormal plasma cells:

• Monoclonal protein

• Bone pain pathological factures

 hypercalcemia: confusion, weakness, lethargy, constipation and polyuria

• Plasma cell

Multiple Myeloma

neoplasm: proliferation of Bcell clone secretes and synthesizes a single homogenous Ig or its fragments • IL-6: potent growth

factor for myeloma • Myeloma cells

secrete: osteoclastactivating factor (OAF), TNF & IL-1  osteolytic lesions

• 98% of cases

>40yrs • Peak incidence in

7th decade • << Men • <
(paraprotien) - IgG in ⅔ & IgA in ⅓ of cases; in serum and/or urine • Immuneparesis:

• Features of anemia

normal serum Ig levels (IgG, A, M) 

• Recurrent infections

• Urine contains Bence

• Protineaceous deposits from

Jones proteins in 2/3

heavy Bence-Jones protienuria, hypercalcemia, uric acid & amyloid  Renal failure (myeloma kidney)

• Plasma cells in BM

• Abnormal bleeding tendancies:

radiographically as punched-out defects, usually 1 to 4 cm

Myeloma protein interferes w/ platelet fn & coagulation factors  RBCs to stick to one another in linear arrays (rouleaux) • Amyloid disease  diarrhea,

macroglossia & carpal tunnel

BM Aspirate:

Marrow cells largely replaced by plasma cells, incl forms w/ multiple nuclei, prominent nucleoli & cytoplasmic droplets containing Ig Occasional pts w/ “indolent myeloma” can survive for many years

• Multifocal destructive

bone tumors composed of plasma cells (plasmacytoma) throughout the skeletal system (axial)

Karyotypic abnormalities are:

( rel="nofollow">20%) w/ abnormal forms

>30% of bone cellularity :

• Deletions of 13q

• Plasma cells with a

• Bone lesions appear

perinuclear hallow (due to prominent Golgi app) & eccentric nucleus

• t(14q32) involving

• Normochromic,

normocytic or macrocytic anemia • Rouleux formation:

Ig heavy chain

Chemo w/ eg Melphalan alkylating agents induce remission in 50%-70% pts, but the median survival still only 3 yrs Poor Prognosis: •  Serum IL-6 • Monosomy chrom 13

• Plasmablasts

• Pts with bony  lesions

• Bizarre multinucleated

• Untreated: 6-12 months

cells • Russell bodies

(cytoplasmic inclusions) • Dutcher bodies (nuclear

inclusions)

• High ESR • Serum calcium

levels in 25% of cases •  Serum IL-6 in

pts w/ active disease

Dysregulated synthesis & secretion of Ig  cytological variants: • Flame cells • Mott cells Grossly: gelatinous, soft, red tumor masses

• t(2;5)(p23; q35) • Associated with

Lymph Node Biopsy: Anaplastic Large Cell Lymphoma

Adult T-Cell Leukaemia/ Lymphoma

• T-cell or null cell

phenotype

• Mature T-cell

(ATLL)

• Common in

children

HTL V-1 endemic in parts of Japan & the Caribbean; disease is rare in people who have not lived in these areas

• Often comprises large

Follows an aggressive course, characterized by systemic symptoms and extranodal involvement

anaplastic cells CD 30 +ve T-cells • Some cells contain

horse-shoe shaped nuclei & voluminous cytoplasm

ALK gene rearrangements on chromosome 2  formation of a chimeric gene encoding the ALK fusion proteins (behave as active Tyrosine Kinases)

Acute presentation as: • Lymphadenopathy • Hepatosplenomegaly

Consistent CD4+ phenotype

• Skin lesions (cutaneous

infiltration)

ATLL-1 lymphocytes:

• Hypercalcemia

• Associated with

Combination of chemotherapy may be tried, however the prognosis is poor

HTLV-1 infection Antiretroviral drugs may have a valuable role

Bizarre morphology with a convoluted, clover-leaf (flower cells) nucleus

Mycosis Fungiodes & SS: Chronic cutaneous lymphoma presents with: • Severe pruritis • Chronic cutaneous

Mycosis Fungoides

CD4+ Helper T cell lymphoma • Characterized by a

marked predilection to involve the skin

• Psoriasis- like lesions

Clinically, cutaneous lesions show three distinct stages: 1- Inflammatory premycotic 2- Plaque phase 3- Tumor phase

Disease progression characterized by extra-cutaneous spread, commonly to LN, spleen, liver & BM Peripheral Smear: In 25% of cases small number of tumor cells can be seen leading to overlap between Mycosis fungoides & Sezary syndrome

• Indolent tumors • Variety of treatment

Skin Biopsy: Infiltration of the epidermis and upper dermis by neoplastic T cells with characteristic cerebriform nuclei

CD4+ T-cells

available including chemo, radiotherapy & a photoactivable drug (psoralens) combined with UV-A light (PUVA) • Median survival: 8-9 yrs • Transformation to large

cell lymphoma of T-cell type occasionally occurs as a terminal event

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Lasanthi Aryasinghe

• CD4+ Helper T cell

tumor

Variant in which skin involvement is manifested as:

• Leukaemic

Sézary Syndrome

• Generalized pruritic, exfoliative

manifestation of Mycosis fungoides

erythroderma affecting palms, soles, face- Red Man syndrome

Characterized by a marked predilection to involve the skin

RS Cells are activated B-cell w/ Ig gene rearrangements Distinctive neoplastic giant cells: ReedSternberg cells with reactive lymphocyte, histiocytes and granulocytes

Hodgkin’s Lymphoma

• Generalized lymphadenopathy

Bimodal incidence: • Young adulthood (age 15–35) • >55 years old

Clinical S/S:

• <
- Fever 30%: continuous or cyclic

• <<Men except

- Pruritis 25%: often severe

Nodular sclerosis variant <<women HL <1% of cancer worldwide 1/25000

- Weight loss

- Anorexia & cachexia

Classical HL: 1- Nodular sclerosing

4- Lymphocytedepletion

• Normochromic,

Normocytic Anemia • Eosinophilia

Ann Arbor Staging (I-IV, A,B,E): Predictive of prognosis and guides the choice of therapy A- Absence of symptoms in B

• LMP-1 protein

B- Presence of 1 or more of foll: •Unexplained fever >38°C

Cure rate in stage I & IIA is close to 90% • NLPHL best prognosis

followed by MC

Variants RS Cells:

• NS & LR are slowly

progressing and prognosis depends on stage

Mononuclear:

• Leucocytosis (

• Polypoid nuclei (popcorn

neutrophils)

cells) • Specific to Lymphocyte predominant HL

•  Serum Lactate De-

hydrogenase (LDH)

Lympho-histiocytic (L& H cells):

• 1 round nucleus • Large inclusion-like nucleolus

Pleomorphic • Multiple, irregular nuclei • Seen in Lymphocyte depletion HL

Lacunar:

•Night sweats

• LD type has the worse

prognosis

Long-term survivors of chemo and radiotherapy have an increased risk of developing second cancer

•Loss of >10% body wt w/in 6mts

2- Mixed cellularity 3- Lymphocyte-rich

*SEE Mycosis Fungioides*

CD4+ T-cells

• Large (15-45 μm) • Binucleate (mirror image nuclei) • Large pink-staining nucleoli- owl’s eyes • Abundant cytoplasm

- Alcohol-induced pain in areas where disease is present

- Weakness, fatigue

(Latent membrane protein-1) of EBV, has transforming activity

Shows lymphocytic infiltration

• Constitutional symptoms:

2)Orderly contiguous spread: adjacent LNs  Spleen  Hepatic disease Finally BM involvement & extranodal disease-Staging 3) Less peripheral involvement

Skin Biopsy:

Classical Reed- Sternberg Cells (activated B- cells):

discrete enlargement of LNs

- Profuse sweating

regulation common to EBV positive and negative HL

Sensitive molecular analyses have shown that tumor cells are found early in the disease course in the blood, BM, and LN (in Mycosis Fung also)

• Nontender, asymmetrical, firm,

1) Localised to single LN or chain of nodes • NF-ĸB up

Peripheral Smear: Shows circulating T lymphoma cells “Sezary cells” with characteristic deep nuclear clefting: cerebriform nuclei

• Cytokines

secreted by RS cells cause accumulation of reactive cells like IL-6, IL-13, TNF

E- Localized extranodal (ie tissue other than LN, thymus, spleen, Waldeyer’s Ring, appendix or Peyer’s patch) extension from mass of nodes

• Folded or multilobate nuclei • Surrounded by abundant pale

cytoplasm • Predominantly in Nodular Sclerosis

• Lacunar variant of RS

cells • Commonly occurs

Nodular Sclerosing type

Most common type 65-70% of HLs

in adolescents and young adults • Rarely associated

RS cells: • +ve: CD15 & 30 • -ve: CD 45, B & Tcell markers

• Involves lower cervical,

supraclavicular and mediastinal LN

with EB virus

Prognosis is excellent

• Collagenous (fibrotic)

bands dividing the LN parenchyma into nodules

• Classical RS cells and

Mononuclear cells are plentiful

• << Males,

Mixed Cellularity type

20-25% of HLs

• Older age group • Strong EBV

association

LymphocyteRich type

• Frequent (40%)

Uncommon form

association w/ EBV

• Usually present with systemic

symptoms and advanced stage

• Diffuse effacement by a

heterogeneous cellular infiltrate: - Small lymphocytes, - Eosinophils - Plasma cells - Benign macrophages

Identical to NS: RS cells: • +ve: CD15 & 30 • -ve: CD 45, B & Tcell markers

• Diagnostic or Classical

Strong EBV assoc

Prognosis is very good

Very good to excellent prognosis

RS cells & Mononuclear cells frequently present

• Predominantly in

older patients Lymphocyte Depletion Type

Least common type

• <
• Paucity (shortage) of

Overall prognosis is poor as pt presents in advanced stage with systemic symptoms

lymphocytes & relative abundance of RS cells or Pleomorphic variants

associated

Nodular Lymphocyte Predominance Hodgkin's Lymphoma (NLPHL)

• Nodular infiltrate • << Young males

Uncommon

• No EBV

association

• Typical RS cells are

extremely difficult to find • L&H or popcorn RS cells

seen

In contrast to all other forms of HL; L&H variants show: •B cell marker: CD20 •Germinal center cell-specific transcriptional factor: BCL6

Excellent prognosis

A small number of cases transform to: Large B cell lymphoma

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Lasanthi Aryasinghe

BM aspirate: Dyserythropoiesis

•Acquired neoplastic

disorders of multipotent hematopoietic stem cells BM aspirate shows: Characterized by: • Ineffective haemopoiesis • Peripheral blood cytopaenias • Single or multiple lineage dysplasia

Myelodysplastic Syndromes

• It is preleukaemic

& may progress to AML, although death often occurs before

• Dyserythropoiesis

In most cases disease arises de novo (1° MDS), but in a significant proportion chemo and/or radiotherapy has been given for another hematological disease, lymphoma or solid tumor (2° MDS) • 50% pts >70yrs

FAB Classification: • Based proportion

of cells in PB & BM

Nucleated red cell progenitors with multilobulated or multiple nuclei

• <25% are <50yrs • <<Males

• Anemia – nonresponsive to

treatment (Refractory Anemia)

• Dygranulopoiesis • Dymegakaryopoeisis

• Sometimes neutropenia &

thrombocytopenia may be present w/out anemia (Refractory cytopenia) • Recurring infections: granulo-

cytes are  and show impaired chemotatic, phagocytic & adhesive function • Spontaneous bruising or

bleeding • May be asymptomatic • In CMML: splenomegaly, gum

hypertrophy, lymphadenopathy

Blood Film shows: • Pancytopaenia: RBCs

are macrocytic or dimorphic • Reticulocyte count

Dygranulopoiesis

•  Granulocytes w/

• Partial or total loss of

chromosomes 5,7 or Y • Trisomy 8 • 20% RAS oncogene

mutation (N-RAS)

lack of granulation • Pelger abnormality:

• 15% FMS mutation

single or bilobed granulocyte nuclei • Platelets may be

large or small

• Refractory Anemia,

Ring sideroblasts w/ Fe laden mitochondria (Prussian Blue or Perl’s)perinuclear granules

Pseudo-Pelger-Huet cells neutrophils with only two lobes ( normal 3 to 4)

•Single or multilineage

Ring Sideroblasts/ Excess Blasts, RAEB in transformation, Chronic Myelomonocytic Leukemia (CMML)

dysplasia Dymegakaryopoeisis

Megakaryocytes with multiple nuclei instead of normal single multilobated nucleus Group of conditions arising frm pluripotent stem cell

4 Types of MPDs: • Splenomegaly • Cellular phase: Hypercellular

BM with PB cytosis

Characterized by: Chronic Myeloproliferative Disorders

•Clonal proliferation

of one or more haemopoietic components in the BM, PB, liver,spleen • Slow indolent progression (relative to ALL)

<< Middle aged Elderly individual

• Fibrotic and/or leukaemic

phase: progressive BM fibrosis

ONLY CML shows low NAP scores; PCV & MF have high NAP

• Chronic Myeloid

Leukaemia (CML) • Polycythaemia Rubra

Vera (PCV) • Essential

Thrombocythaemia (ET) • Myelofibrosis (MF)

PCV, ET & MF are nonleukemic MPDs

Clonal disorder of the pluripotent stem cells Peripheral Blood Smear CML is triphasic: 1- Chronic (Stable) Phase)

Chronic Myeloid Leukaemia (CML)

2- Accelerated Phase: Anaemia, thrombocytopenia,  basophils, eosinophils or • < 40-60 years blast cells in PB &/or • < Atom bomb BM survivors in Japan 3- Blast crises: • >20% blasts in blood &/or BM • Enlarged spleen &

fibrotic marrow • New chromosome

abnormalities (eg double Ph chrom) • Transformation/

Metamorphosis to AML (70% of cases) or ALL (30%)

Peripheral Blood: • Leucocytosis >50,000  Total body myeloid cell mass  clinical features: • Hypermetabolism (weight loss,

lassitude, nightsweats, anorexia) • Massive splenomegaly

• Abelson proto-oncogene

ABL moved to the BCR gene on 22 + part of 22 moves to 9

myeloid cells(Neutro, Baso, Eosino, Pro/ meta/myelocytes) normocytic anaemia

Neutrophils in different stages of maturation

• Bleeding: impaired platelets

function (bruising, epistaxis, menorrhagia) • Gout/renal impairment due to

hyperuricaemia from excessive purine breakdown

• BCR-ABL chimeric fusion

gene • Chimeric gene encodes

• Anaemia (pallor, dyspnoea and

tachycardia)

• Reciprocal translocation

t(9;22)(q34;q11)

• Full spectrum of

•Normochromic

CML characterized by Philadelphia chromosome

BM exam: Hypercellular with granulopoeitic predominance

Bone Marrow Biopsy

• Ph +ve reduce the

• NAP Score: low • Ph chromosome: is

+ve on cytogenetic analysis of blood/BM •  Serum Uric acid

 chimeric protein with tyrosine kinase activity

Hypercellular with granulopoeitic dominance

adherence of CML progenitor cells to the BM stromal layers compared to their normal cell counterparts  autonomous proliferation of CML progenitors due to their premature escape from physiological inhibitory influences in the stem cell niche

• 5q-Syndrome:

Good prognosis

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Lasanthi Aryasinghe

Bone Marrow hypercellular  replaced with leukaemic blasts which leads to: • General - Bone pain, fever

FAB Classification:

Acute Myelogenous Leukaemia

° of maturation (M0-M3) and lineage of leukaemic blasts (M4-M7) taken into account, using morphology and cytochemistry

WHO Classification: Cytogenetic, morphologic and clinical features (prior haematologic disorders) in defining disease entities

• All age groups • 80% of adult

leukaemias

• BM failure Cytopaenias:

(Anaemia, Thrombocytopaenia, Neutropaenia)

• 10- 15% of

•Extramedullary organ infiltration

childhood leukaemias

monocytic component AML-M5: - Gingival hypertrophy - Skin infiltration - Meningeal leukaemia - Solid tumor mass (chloroma)

Can arise de novo (1° AML), but can develop from MDS, chemo and/or radio-therapy or hematological disease

• Lymphadenopathy • Hepatomegaly, Splenomegaly • Coagulopathy: DIC in Acute

Promyelocytic Leukaemia (AMLM3) from tissue thrombplastin

M6: Erythroleukaemia (DiGuglielmo's disease)

Alterations in genes encoding for critical transcription factors  arrest of terminal differentiation

• PB Morphology:

- Blast count >20% = Acute leukemia - Blast type: Myeloblast- AML Lymphobast- ALL • BM Morphology • Cytochemistry:

- MyeloPeroxidase (MPO) stain +ve myeloid -ve  lymphoid

Most common: • t(8;21) - CBF complex • AML-M4 Eo:

Delicate chromatin, prominent nucleoli, and fine azurophilic cytoplasmic granules

(Flow Cytometry) • Cytogenetic analysis (Chromosomal Banding) • Molecular genetic analysis (FISH)

inv (16) - CBF 1β gene

AML M3 - BM shows neoplastic promyelocytes with abnormally coarse and numerous azurophilic granules. Needle like Auer rods

Poor Prognosis: • Translocations

• AML-M3: Promyelocytic

AML M1: CD 34, 64, 33

- PAS stain “block positivity” in lymphoid • Immunophenotyping

Myelomonocytic with abnormal eosinophils:

t(15;17) (PML; RARA) Retinoic acid receptor –α gene (RAR α) fuses to a protein PML  chimeric gene block in myeloid differentiation All trans retinoic acid (ATRA) used for treatment • FLT3 Mutations 

activates tyrosine kinase This synergistic genetic “hits”  cellular proliferation along with block in differentiation

with an 11q23 breakpoint and MLL gene rearrangement •Therapy related:

Alkylating agents & Topoisomerase II inhibitors