mt0831 complete hematology report compilation
TRANSCRIPT
Veah Deborah CruzemJustine Chlarissa Del RosarioArianne Mirabueno
MT0831
• a form ofhematopoiesis inwhich white bloodcells (WBC,or leukocytes) areformed in bonemarrow located inbones in adults andhematopoieticorgans in the fetus.
LEUKOCYTES
∗ White blood cells∗ Defend the body against both infectious
disease and foreign materials∗ Five different types exist∗ All produced and derived from Hematopoietic Stem
cell∗ Two categories:
∗ Granulocytes & Agranulocytes
Leukocytes
∗ Presence of granules∗ Released from the bone marrow by the
regulatory complement proteins.∗ Includes:
∗ Neutrophils∗ Eosinophils∗ Basophils
Granulocytes
∗Absence of granules∗ Includes:
∗Monocytes∗Lymphocytes
Agranulocytes
Neutrophil Maturation
Myeloblast<1% in the normal bone marrow
15-20 µm in size
Nucleus: delicate with prominent nucleoli
Cytoplasm: contains rough endoplasmicreticulum, a developing Golgi apparatusinitial presence of primary or azurophilicgranules
Granules color positively formyeloperoxidase
Myeloblast
MYELOPEROXIDASE –an enzyme that occurs inprimary granules ofpromyelocytes,myelocytes, andneutrophils and exhibitsbactericidal, fungicidaland viricidal properties.
o The cell is incapable ofmotility, adhesion, andphagocytosis
Promyelocyte(Progranulocyte)
1%-5% in the bone marrow
Greater than or equal to 20 µm
Nuclear chromatin: shows slightclumping; nucleoli began to fade
Promyelocyte
This activates neutralproteinases cathepsin G,elastase, and proteinasesfor killing to take place.
Neutrophilic Myelocyte
<10% of total BM cell population
Last cell capable of mitosis
Nucleus: round to oval with flattened sidenear a well-developed Golgi apparatus
Nuclear chromatin: shows clumping;nucleoli is no longer visible
“DAWN OFNEUTROPHILIA” – faintblush of pink within thecytoplasm; caused bythe granules
Neutrophilic Myelocyte
Neutrophilic Myelocyte
Some important compounds within thesecondary granules:
Thrombospondin receptor
β2-microglobulin
Apolactoferrin
Lysozyme
Plasminogen activators
Neutrophilic Metamyelocyte
After cessation of all active DNA synthesis
Nucleus: indented
13%-22% of BM
Synthesis ofgelatinasegranule by theend of stagedevelopment
Contain lysozymeand acetyltransferase
Neutrophilic Metamyelocyte
Neutrophilic Band
Nonsegmented form
40% of WBCs in BM
Absence of nuclear segments composedof dense heterochromatin
Represents the almost mature cell
Possesses full motility,active adhesion properties,and some phagocytic ability
Membrane maturity:changes in cytoskeleton,changes in surface charge,and presence of receptorsfor complement (CRs),specifically for CR1 and CR3.
<6% of WBCs in peripheralblood
Neutrophilic Band
Neutrophilic Band
Presence of secretory vesicle, animportant store of surfacemembrane-bound receptors andmay be functional in antigenpresentation
Endocytosis
PolymorphonuclearNeutrophil
Many-shaped nucleus
Nucleus: easily deformable; visiblesegments; some appear grossly twistedand folded
Present in the bone marrow and in themarginating and circulating pools
50%-70% in the peripheral blood
Positive for the adhesion moleculesCD62, CD11a/CD18
Performs phagocytosisand pinocytosis
Neutrophils areattracted are attractedto particles by severalmechanisms:
Chemotaxis
Complement fixation
PolymorphonuclearNeutrophil
*First recognizable cell.
*Diameter between 14 and 18µm
*Occupied by a large oval nucleus
*Nucleus is composed of very fine nonaggregated chromatin and possesses 3 or more nucleoli.
* Cell size, 12 to 20 µm
* Contains a few, as yet undifferentiated, cytoplasmic granules
* Second largest stage in the granulocytic series
*Granules are peroxidase positive
*One to three nucleoli are also visible
* First of the maturation stages of the granulocytic leukocytes normallyfound in the bone marrow
*Granules are seen in the cytoplasm
* Cell is flat and contains increasing numbers of granules as maturationprogresses.
*Appearance of a bent nucleus, cytoplasmic granules
*Absence of visible nucleoli.
Myeloblast Promyelocyte Myelocyte Metamyelocyte MaturedEosinophils
Myeloblast Promyelocyte Myelocyte Metamyelocyte MaturedBasophils
*10-12 microns
*1-3% of circulating WBCs
*Responsible for combatingmulticellular parasites andcertain infections in vertebrates
*Control mechanisms associatedwith allergy and asthma.
*Acid-loving
*Nucleus with 2-3 lobes
*Stained heavily with eosindye used in conventionalRomanowsky stain
*Spends less than 1 week inperipheral blood
*Actively motile
*Acid phosphatase
*Arylsulfatase
*Β-Glucuronidase
*Cathepsin
*Peroxidase
*Phospholipase
EosinophilicGranules Contents
*Water-soluble
*Needle-shape
*Result of eosinophildisintegration
Charcot-LeydenCrystal
* Irregular, s-shaped, bilobednuclei
*8-10 microns
*0-1% of circulating WBCs
*Obscure the cell nucleus
*Large heavily staining granulesstain with basic dyes
*contains anticoagulant heparin
*contains the vasodilator histamine
*plays a role in both parasiticinfections and allergies
*regulates the behavior of T cells
*have protein receptors on theircell surface that bind IgE
*Mastocyte
*Rich in histamine and heparin
* Involved in wound healing anddefense against pathogens.
MAST CELLS
MONOCYTES
MONOCYTEdevelop from thesame precursor asneutrophils -the CFU-GM.cells that are madein the bone marrow,and they spreadthrough the body inone to three days.
MONOCYTEMATURATION
MONOBLAST
the earliestprecursor arisingfrom a committedstem cell in themonocytic series,which developsinto thepromonocyte.
PROMONOCYTE
• a cell in an intermediatestage of developmentbetween a monoblast anda monocyte
• Size: 12-20 microns indiameter.
• Nucleus: The nucleus isoval or indented and lightpurple.
• Cytoplasm: Thecytoplasm is gray-bluewith fine dust likeazurophilic
MATURED MONOCYTE
incapable of mitosis and enter the circulation.Size: 12-20 microns in diameter.Nucleus: The nucleus is round or kidney-shaped, but can be deeply indented or havetwo or more lobes.Cytoplasm: foamy blue grayFunction:take longer time to get to site of infection butarrive in larger numbersbecome wandering macrophages once theyleave the capillariesdestroy microbes and clean up dead tissuesfollowing an infection
LYMPHOCYTES
LymphocytesHuman blood leukocytes whose site of
development is not solely the bone marrow,but also tissues referred to as primary andsecondary lymphoid organs
Thymus and bone marrowSpleen, Peyer’s patches, Waldeyer ring of
the tonsils and adenoids, and lymph nodesand nodules scattered throughout the body
Hand mirror shape is a result of theircharacteristic form of locomotion
DEVELOPMENTThe thymus and bone marrow give rise
to lymphocytes, foster differentiationand are independent of antigenicstimulation.
T cells – cells that develop under theinfluence of the thymus; have a specific,unique set of receptors and responses
B cells – derived from BM ad have adifferent set of functions and capabilities
Plasma cell – end cell of B lymphocytematuration
B CELL
T CELL
PLASMA CELL
LymphocyteMaturation
Lymphoblast to ProlymphocyteLYMPHOBLAST
10-18 µm in size Nucleus: round to oval, with loose chromatin and
one or more active nucleoli. Cytoplasm: scanty and has basophilia
proportional to amount of RNA present
PROLYMPHOCYTE Slightly more clumped chromatin, lessened
nuclear prominence, change in thickness ofnuclear membrane
Lymphoblast Prolymphocyte Lymphocyte
Small lymphocyteMost commonapprox. 9 µm in sizeNucleus: round to oval; block type
chromatin patternNondiving or resting
LYMPHOCYTE
LYMPHOCYTEMedium Lymphocyte
11-14 μm in diameter Contains azurophilic granules that are more
clearly discerned nondiving
LYMPHOCYTELarge lymphocyte
Rarest in PB 15 μm Has a deeper shade of blue when stained May be part of natural killer cells
1. The first of the maturation stages of the granulocytic leukocytesnormally found in the bone marrow.
a.Myeloblast b. Promyelocyte c. Myelocyte d. Metamyelocyte
2. It is characterized by the appearance of abent nucleus, cytoplasmic granules, and the absence ofvisible nucleoli.
a.Myeloblast b. Promyelocyte c. Myelocyte d. Metamyelocyte
3. Cells that develop under the influence of the thymus, have aspecific, unique set of receptors and responses.
a. T cells b. B cells c. Plasma cells d. Mast cells
4. Tissue equivalent of circulating basophil. Involved in allergicinflammation and initiate localized and system anaphylaxis.
a. T cells b. B cells c. Plasma cells d. Mast cells
5. Size of matured basophil.
a. 10-12 microns b. 8-10microns c. 10-15 microns d. 6-9microns
Terminologies Quantitative
Change in number Terminology
Cytosis / philia Increase in number
Cytopenia Decrease in number
LEUCOCYTES BENIGN DISORDERS Quantitative changes (LEUKOCYTOSIS) Definition
Raised TWBC due to elevation of any of a singlelineage.
Note: elevation of the minor cell populations can occurwithout a rise in the total white cell count.
Normal reference range (adult 21 years) 4.5 -- 11.0 x 109/L
LEUCOCYTES BENIGN DISORDERS Quantitative changes (LEUKOPENIA)
DefinitionTWBC lower than the reference range for the age isdefined as leucopenia Leukopenia may affect one or more lineages and it is
possible to be severely neutropenic or lymphopenicwithout a reduction in total white cell count.
LEUCOCYTES BENIGN DISORDERS Quantitative changes (contd.)
GranulocytosisIncrease in the count of all or one of thegranulocytic component
Neutrophils Basophils Eosinophils
AgranulocytosisDecrease in the count of all or one granulocyticcomponent
Leukocytes Leukocytes
Phagocytes Granulocytes
Neutrophils Eosinophils Basophils
Mononuclearphagocytic cells Monocytes Macrophage and
denderetic cells Lymphocytes
B-cells T-cells
N
E
B
LM
Band
P
Neutrophils Count 2.5 - 7.5 x
109/l Granular cytoplasm Transient stay in
blood Major phagocytic
role Bacterial killing
3-5 lobes of nucleus
Disorders of Neutrophil Neutrophilia
Infection (Bacterial) Inflammatory conditions Neoplasia Metabolic conditions
Uraemia Haemorhage / haemolysis Corticosteroids Marrow infiltration
Haematologicalmalignancies
Chronic Myeloid Leukaemia Myeloproliferative disorder
CML
MM M
N
Baso
Myeloid malignancies
Acute Myeloid Leukaemia(AML M-3)
Chronic Myeloid Leukaemia
Disorders of Neutrophil
Neutropenia Count < 1.5 x 109/l Drugs Chemotherapy Viral infection Inherited disorders
Morphological abnormalities Pelger-Huet anomaly May-Hegglin anomaly Chediak-Higashi syndrome
Neutrophilia Transiently with stress and exercise by a shift of
neutrophils from the marginating pool to thecirculating pool. Infection Toxins: metabolic (uremia), drugs, chemicals Tissue destruction or necrosis: infarction, burns,
neoplasia, etc Hemorrhage, especially into a body cavity Rapid hemolysis
Neutropenia Aplastic anemia Toxins that damage marrow Infection Viral (Hep-B), Mycoplasma etc. marrow infiltration by infections or carcinomas,
Radiation therapy Chemotherapy Hematologic malignancies such as leukemias Myeloproliferative disorders Congenital disorders Increased neutrophil destruction as in
Splenomegaly, Immune destruction
Lymphocytes Count varies with
age1.5 – 3.5 x109/l The subset cells are
B-cells Antibody mediated
immunity
T-cells Cell mediated immunity
NK cells
Disorders of lymphocytesBenign disorders Lymphocytosis
Viral infections Bacterial infections Protozoal infections
Lymphopenia Marrow failure (drugs, irradiation) Infections (viral infections)
Immune-deficiency syndromes Antibody deficiency Cell mediated immune defieciency Combined cell and antibody immune deficiency
Disorders of Lymphocytes Infectious
mononucleosis Epstein-Barr virus
infection
Autoimmunelymphoproliferativesyndrome
Disorders of LymphocytesMalignant disorders Acute lymphoblastic
(ALL) leukemia Chronic lymphocytic
leukemia (CLL)
Lymphomas Non Hodgkin’s
lymphoma Hodgkin’s disease
ALL
CLL
LymphocytosisNormally be observed in infants and young
children.Acute infections, including pertussis,
typhoid, and paratyphoid Infectious mononucleosis, with "atypical"
lymphocytosisViral infections, including measles, mumps,
adenovirus, enterovirus, and Coxsackie virusToxoplasmosis
Lymphopenia Immunodeficiency syndromes, including
congenital (DiGeorge syndrome, etc)and acquired (AIDS) conditions
Corticosteroid therapyNeoplasia, including Hodgkin's disease,
non-Hodgkin's lymphomas, andadvanced carcinomas
Radiation therapyChemotherapy
Monocytes Count is 0.2-0.8 x
109/l Functions
Antigen presentation Cytokine production Phagocytosis
Disorders of Monocytes Monocytosis
Benign Chronic bacterial infection
Malignant Chronic Myelomonocytic Leukaemia CMML
Monocytosis Infections: such as brucellosis,
tuberculosis and rickettsiaMyeloproliferative disordersHodgkin's diseaseGastrointestinal disorders, including
inflammatory bowel diseases andsprue
Eosinophils
Count 0.2 – 0.8 x 109/l Bilobed nucleus Phagocytic activity is
low Modulation of
hypersensitivity andallergic reactions
Disorders of Eosinophil Eosinophilia
>0.8 x 109/l Allergic reactions Parasitic infections Malignancy Inflammatory conditions Myeloproliferative disorders Hypereosinophilic syndrome
Basophils
Count 0.1 – 0.2 x 109/l Bilobed nucleus Nucleus is hided
behind the granules Inflammatory
response Basophilia is seen in
Myeloproliferativedisorders (CML)
EosinophiliaAllergic drug reactionsParasitic infestations - with tissue invasionExtrinsic asthmaHay feverExtrinsic allergic alveolitis ("farmer's lung“)Chronic infectionsHematologic malignancies: CML,
Hodgkin's disease
Eosinopenia, Monocytopenia& Basopenia
Acute stress reactions with increasedglucocorticoid and epinephrinesecretion
Cushing's syndrome withcorticosteroid therapy
Steroid therapyAcute inflammation
Leukemoid Reaction:Definition A leukemoid reaction (LR) is a hematological disorder,
defined by a leukocyte count greater than 50,000cells/mcL with reactive causes outside the bone marrow
LR is characterized by a significant increase in matureneutrophils in the peripheral blood and a differentialcount showing marked left shift.
The diagnosis of LR is based on the exclusion of chronicmyelogenous leukemia (CML) and chronic neutrophilicleukemia (CNL).
NONMALIGNANT LEUKOCYTEDISORDERS
Many bands, metamyelocytes, and myelocytes areseen
Occasional promyelocytes and myeloblasts maybe seen.
This condition resembles a chronic myelocyticleukemia (CML), but can be differentiated fromCML based on the fact that in leukemoid reactions:
There is no Philadelphia chromosome The condition is transient There is an increased leukocyte alkaline
phosphatase score (more on this later) Leukemoid reactions may be seen in tuberculosis,
chronic infections, malignant tumors, etc.
Leukemoid Reaction MajorCauses: Infections Clostridium difficile colitis Severe shigellosis Disseminated tuberculosis Serious bacterial infections
Work up of LR should include cultures of blood,sputum, and bone marrow for common bacteria andmycobacteria. Stool cultures should not beoverlooked.
Leukemoid Reaction MajorCauses: Infections
C. difficile colitis with an LR appears to beassociated with a much higher mortality rate (approx50%).
Leukemoid Reaction MajorCauses: Drugs/Toxins
Corticosteroids Minocycline Recombinant hematopoietic growth factors Ethylene glycol
Leukemoid Reaction Major Causes:Malignancy
Carcinomas (lung, oropharyngeal, gastrointestinal,genitourinary)
Hodgkin's lymphoma Melanoma Sarcoma
Leukemoid Reaction Major Causes:Malignancy
Leukemoid reactions can present simultaneouslywith malignancy, late in the course of the disease, orprecede the diagnosis by as many as 4 years.
In a study of 227 patients with carcinoma of thelung, 33 patients (14.5%) were diagnosed withtumor-related leukocytosis and 6 patients (2.6%)with LR.
Leukemoid Reaction Major Causes:Malignancy
The mechanism of the generation of an LR inassociation with a neoplasm has not been fullyelucidated.
It is likely that various cytokines produced irregularly bythe tumor cells, including granulocyte colony-stimulatingfactor (G-CSF), granulocyte-macrophage colony-stimulating factor (GMCSF), and interleukin 6 (IL-6), mayunderlie the pathogenesis of LR in such conditions.
Leukemoid Reaction versus CNLversus CML
CML:
immature cells, basophilia or monocytosis decreased leukocyte alkaline phosphatase (LAP) score bcr/abl translocation.
The differential diagnosis between LR and CNL may bedifficult or even impossible because both conditionsshare:
identical morphological features increased LAP score absence of the bcr/abl translocation.
Leukemoid Reaction versus CNLversus CML: The Smear
In CML, there are more immature cells, basophils,and eosinophils.
In LR, consist mostly of mature neutrophils. Thedifferential count discloses a marked left shift,presence of myelocytes and metamyelocytes.
In CNL, there is marked neutrophilia with noimmature cells
Leukemoid Reaction versus CNLversus CML: The Bone Marrow
In CML, basophilia, eosinophilia, monocytosis, or even aminimum percentage of blasts are characteristic.
Increased cellularity with myeloid hyperplasia is seen inboth LR and CNL.
In LR there is marked proliferation and orderlymaturation of all normal myeloid elements with normalmorphology, without fibrosis.
Leukemoid Reaction versus CNLversus CML: The Bone Marrow
Similar morphological features are present in CNLand LR, but a packed bone marrow biopsy, togetherwith a slight increase in reticulin fibrosis, may helpdifferentiate it from a reactive process.
Leukemoid Reaction versus CNLversus CML: LAP score
LAP is an enzyme present in the cytoplasmicmicrosomes of neutrophils, bands,metamyelocytes, and myelocytes, but not inlymphocytes or monocytes.
Immature neutrophils, such as those observed inCML, have decreased LAP scores.
Stimulated neutrophils of an LR have high LAPscores.
Leukemoid Reaction versus CNLversus CML: LAP score
Leukocyte alkaline phosphatase (LAP) score is highin infection/inflammation, polycythemia vera andCNL.
LAP score is low in CML.
Leukemoid Reaction versus CNLversus CML: Cytokine Levels
Although G-CSF, GM-CSF, and IL-6 are notincluded in diagnostic criteria for CNL,measurement of enzyme-linked immunosorbentassay (ELISA) have been used to elucidatecytokine-producing tumor and the developmentof an LR.
Generally CML and CNL patients havesignificantly low G-CSF levels, suggesting thatneoplastic granulopoiesis can exert asuppressor effect on G-CSF synthesis.
Leukemoid reaction
Leukemoid reactions are characterized by blasts, promyelocytes,myelocytes, and metamyelocytes in the peripheral blood.
Leukemoid reactions may be secondary to benign or malignantconditions.
A leukoerythroblastic reaction is similar to a leukomoidreaction with the addition of nucleated red blood cells. Aleukoerythroblastic picture indicates severe disruption ofthe marrow and is common in myelofibrosis (primary orsecondary).
In infants a leukoerythroblastic reaction suggestssevere hemolytic anemia, such as erythroblastosis
END Prepared By:
•Savannah Lima
•Johnpaul Mojica
•Gurpreet Singh
Questions
1.) a hematological disorder, defined by a leukocyte count greaterthan 50,000 cells/mcL with reactive causes outside the bonemarrow.
A.neutrophilia B.eosiniophilia C.leukemoid reactionD.neutropenia
2.)term used for increase in neutrophils A.basophilia B.neutrophilia C.neutropenia D.eosinophilia 3.)an agranulocyte with horse shoe shaped nucleus. A.lymphocyte B.monocyte C.segmenters D.PMN 4.)normal value for TWBC A.4.5-11x10 9 B.2.5-11x10 9 C.6.5-11x10 9 D. 9.5-11x10 9
5.)these are drugs/toxins associated with leukemoid reaction,EXCEPT
A.corticosteroids B.rifampin C.ethylene glycolD.tylenol
#1 ADAO, Dyrelle#6 CASTILLO, Gileen Grace I.
#11 DELA CRUZ, Sharmila Mae R.MT0831
Dra. Asilo
Qualitative Non-Neoplastic WBC Disorder
∗ Recessive disorder∗ Azurophilic granules in one or all cell types∗ Inclusions: Lymphocyte w/ no neutrophil
abnormalities
Alder-Reilly Anomaly
∗ Dense, Large, dark lilac, azurophilic granules(neutrophil, eosinophil, basophil, occasionallylymphocytes and monocytes)
∗ Granules• Larger than normal azurophilic and basophilic
granules• Lilac with Wright-Giemsa Stain• Metachromatic with Toluidine Blue• Evenly distributed throughout cytoplasm
Morphology
∗ Resemble Toxic Granulation∗ Obscure the nucleus- function normally
∗ Inclusions:∗ more frequently seen in Bone marrow∗ Lymphocyte inclusion: less numerous∗ Basophilic inclusion: surrounded by clear halo & stain
metachromatically
Morphology
Normal Neutrophil
Neutrophil with Alder-ReillyAnomaly
Alder-Reilly Anomaly withAzurophilic Granules
Neutrophil Lymphocyte Monocyte
ToxicGranulation
∗ Mucopolysaccharide Degradation:∗ Hunter’s Syndrome (Mucopolysaccharidosis Type II /
MPS II)∗ Hurler’s Syndrome (Mucopolysaccharidosis Type I/
MPS I)∗ Maroteaux–Lamy syndrome (Mucopolysaccharidosis
Type VI/ MPS VI)
Associated Disease
Hurler’s Syndrome
Hurler’s Syndrome
∗ Aka Mucopolysaccharidosis Type II / MPS II∗ Named after physician Charles A. Hunter∗ X-linked recessive∗ Deficiency or absence of the lysosomal enzyme
iduronate-2-sulfatase (I2S)∗ Physical Appearance:
∗ Coarse facial features (gargoylism)∗ nose with a flattened bridge, and an enlarged tongue∗ Large head (macrocephaly)∗ Joints of fingers, arms, and legs held in partial flexion∗ Enlarged abdomen (due to enlarged liver and spleen)∗ No cloudy corneas
Hunter’s Syndrome
Hunter’s Syndrome
∗ Aka Mucopolysaccharidosis Type VI/ MPS VI∗ Name after Pierre Maroteaux and Maurice Lamy∗ Deficiency in arylsulfatase B (ARSB)∗ Onset before age 3∗ No current treatment for the syndrome∗ Physical Appearance:∗ clouded corneas∗ deafness∗ thickening of the dura
Maroteaux–Lamy syndrome
Maroteaux–Lamy syndrome
∗The following syndromes areassociated with Alder-ReillyAnomaly EXCEPT:a.Hunter syndromeb.Hurler syndromec.Myeloperoxidase deficiency syndromeMaroteaux-Lamy syndrome
Question #1
∗The appearance of Alder-ReillyAnomaly is difficult to distinguishfrom:a.Dohle bodiesb.May-Hegglin Anomalyc.Toxic granulationd.Chediak-Higashi syndrome
Question #2
∗Which of the following isassociated with Alder-Reillyinclusions?
a. membrane defect of lysosomesb. Dohle bodies and giant plateletsc. two-lobed neutrophilsd. mucopolysaccharidosis
Questions #3
∗The cytoplasmic abnormality of thewhite blood cell of Alder-Reillyanomaly is found in the:a. endoplasmic reticulumb. lysosomesc. mitochondriad. ribosomes
Question #4
∗Where can Alder-Reilly inclusionsbe frequently seen?a. Peripheral bloodb. Bone marrowc. Spleend. Kidney
Question #5
Chédiak-Higashi syndromeChédiak-Higashi syndrome
Azarcon, dyna mae j.Zipagan, valeriemt0831
Chédiak-Higashi syndromeChédiak-Higashi syndromeEponymEponym
Alexander Moisés Chédiak--- Cuban physician and serologistOtokata Higashi--- Japanese pediatrician
Chédiak-Higashi syndromeChédiak-Higashi syndromeBackgroundBackground
Beguez Cesar in 1943Steinbrinck in 1948Chédiak in 1952Higashi in 1954
rare childhood autosomalrecessive disorder
Chédiak-Higashi syndromeChédiak-Higashi syndromeBackgroundBackground
hypopigmentation of theskin, eyes, and hair; prolongedbleeding times; easy bruisability;recurrent infections; abnormalnatural killer cell function; andperipheral neuropathyMorbidity results from patientssuccumbing to frequent bacterialinfections or to an accelerated-phase lymphoproliferation intothe major organs of the body
Chédiak-Higashi syndromeChédiak-Higashi syndromeCauseCause
mutations in the LYST geneWhat is the official nameof the LYST gene?The official name of this gene is“lysosomal trafficking regulator.”LYST is the gene's official symbol.What is the normal functionof the LYST gene?provides instructions for making aprotein known as the lysosomaltrafficking regulatordetermine the size of lysosomesand regulate their movement within cells.
Chédiak-Higashi syndromeChédiak-Higashi syndromePathophysiologyPathophysiology
How are changes in the LYST generelated to health conditions?At least 30 mutationsin the LYST geneChildhood formabnormally short, nonfunctional versionof the lysosomal trafficking regulator proteinAdult versionusually change a single protein building block (amino acid) inthe protein
Chédiak-Higashi syndromeChédiak-Higashi syndromePathophysiologyPathophysiology
abnormally large lysosomes andrelated structures in cellsthroughout the body= interferewith normal cell functionscellular structures called melanosomes
(which are related to lysosomes) areabnormally large= melanin is trappedwithin the giant melanosomeslysosome-like structures inside blood cellscalled platelets= abnormal bruisingand bleeding
abnormal lysosomes in nerve cells= neurologicalproblems associated with this disease
Chédiak-Higashi syndromeChédiak-Higashi syndromePathophysiologyPathophysiology
Where is the LYST gene located?Cytogenetic Location: 1q42.1-q42.2Molecular Location on chromosome 1: base pairs235,824,342 to 236,030,219
The LYST gene is located on the long (q) armof chromosome 1 between positions 42.1 and 42.2.More precisely, the LYST gene is located from basepair 235,824,342 to base pair 236,030,219 onchromosome 1.
SYMPTOMS:SYMPTOMS:Children with this condition may have: Albinism Increased infections in the lungs, skin, and mucous
membranes Nystagmus Accelerated phase - (EBV)◦ fever, episodes of abnormal bleeding, overwhelming
infections, and organ failure.
Common: Infections – (mucous membranes, skin,respiratory
tract) Neuropathy
OTHER SYMPTOMS:OTHER SYMPTOMS: Decreased vision Mental retardation Muscle weakness Peripheral neuropathy Nosebleeds or easy bruising Numbness Tremor Uncontrolled bowel movements Seizures Photophobia ataxia
DIAGNOSIS/EXAM/TEST:DIAGNOSIS/EXAM/TEST: Physical exam Biopsy of skin, muscle, and nerves - granules Bone marrow smears - giant inclusion bodies white blood cells (leukocyte
precursor ). Prenatal testing EEG - seizures Brain MRI or CT scan – small brain (atrophy) EMG or nerve conduction velocity testing – delayed
nerve signaling Peripheral blood smear - neutropenia and
hypergammaglobulinemia. Fluorescence cytometric analysis - analysis of cellular
granularity and surfacemolecules
TREATMENT:TREATMENT: no specific treatment Bone marrow transplants Antibiotics- infections Antiviral drugs - terminal phase of the
disease◦ Acyclovir◦Cyclophosphamide◦ prednisone
Vitamin C therapy - improved immunefunction and clotting in some patients.
MORTALITY/MORBIDITY:MORTALITY/MORBIDITY: Death - first decade result of infection, bleeding,
or development of the accelerated lymphomalike phase
The second and third decades – survivalreported
RACE: Affects all races Al-Khenaizan - underreported in persons of darker-
skinned races.
AGE:Usually appear soon after birth or in children youngerthan 5 years.
PHOTOSPHOTOS
Questions:Questions: What do you call the phase where there is a lymphoma like
syndrome?a. slow phase c. latent phaseb. primary phase d. accelerated phase
What is the diagnostic hallmark of Chediak-Higashisyndrome?a. Small inclusion bodies c. Medium inclusion bodiesb. Giant inclusion bodies d. Darkly pigmentedinclusion
What is the medical term for jerky eye movement?a. Hyperhidrosis c. Nystagmusb. seizures d. Ataxia
What is the official name of the gene affected in patientswith Chediak-Higashi syndrome?
a. Lysosome transport regulatorb. Lysosomal trafficking regulatorc. Lysosyme transcriptase regulatord. Lysosomal transferase regulator
What disease form of the Chediak-Higashi syndrome isvery fatal?
a. childhood form c. pregnant formb. teenage form d. Late adulthood form
Prepared by: Valerie S. Zipagan
May Hegglin Anomaly
Chua, CristinaDela Pena, Andrew Vittorio
Guia, Alexa
May-Hegglin anomaly (MHA)
o Also known as Dohle leukocyteinclusions with giant platelets andmacrothrombocytopenia withleukocyte inclusions
o It is a rare genetic disorder of the bloodplatelets that causes them to beabnormally large.
o The anomaly also causes abnormalitiesin the white blood cells knownas leukocytes.
Backgroundo In 1909, Richard May described the
presence of leukocyte inclusions andlarge platelets in an asymptomaticyoung woman.
o In 1945, Robert Hegglin described aman and his 2 sons who were healthybut had a triad consisting ofthrombocytopenia, giant platelets,and leukocyte inclusions (see pictureon next slide)
Background
Blood smear (originalmagnification X2000) in apatient with May-Hegglinanomaly (MHA)demonstrates acharacteristic giantplatelet with poorlydefined granulation. Anormal-sized platelet isalso present. The trilobedneutrophil contains alarge, well-defined,basophilic, peripherallyplaced cytoplasmicinclusion body (resemblinga Döhle body). Used withpermission from Little,Brown
Backgroundo His diagnostic triad was later given the
eponym May-Hegglin anomaly (MHA).
o May-Hegglin anomaly- is an autosomal dominant disorder
characterized by various degrees ofthrombocytopenia that may be associatedwith: purpura and bleeding giant platelets containing few granules and large (2-5 µm), well-defined, basophilic,
cytoplasmic inclusion bodies in granulocytesthat resemble Döhle bodies.
Backgroundo May-Hegglin anomaly
- is one of a family ofmacrothrombocytopeniascharacterized by mutations inthe MYH9 gene.
o The other members of this familyinclude:- Sebastian syndrome- Epstein syndrome- Fechtner syndrome
Pathophysiologyo Patients have a mutation of
the MYH9 gene present inchromosomal region 22q12-13.
o The mutation results in disorderedproduction of nonmuscle myosinheavy-chain type IIA, which leads toinvariable macrothrombocytopeniasecondary to defectivemegakaryocyte maturation
Pathophysiologyo Platelet function in patients with May-Hegglin
anomaly has been reported as normal.o However, in one study, epinephrine response
was described as abnormal in 8 of 15 patientso Leukocyte Döhle inclusion bodies are
visualized on standard Wright stain andappear bright blue and spindle shaped
o Ultrastructural studies reveal that thesebodies consist of clusters of ribosomesoriented along parallel myosin heavy-chainfilaments 7–10 nm in diameter
o Neutrophil function is considered to benormal, and patients have no increasedsusceptibility to infections.
Signs and Symptomso Asymptomatico Minor hemorrhageso Mild leukopeniao Mild reduction in level of blood plateletso Skin hemorrhageo Nosebleedo Excessive oral bleeding during dental
procedureso Headacheo Muscle weakness on one side of body
Signs and Symptomso Intracranial bleedingo Large blood plateletso Mild reduction of level of blood
plateletso Prolonged bleeding timeo Bleeding inside the braino Excessive menstrual bleedingo Easy bruisingo Gums that bleed easilyo Excessive bleeding after operations
o Active bleeding from the mucosalsurfaces may be observed.
o The most common sites of bleedinginclude the mouth and nose.
o Prolonged and excessive bleedingand oozing associated withlacerations and sutures may also beobserved.
Skin Hemorrhage
Nosebleed
Intracranial hemorrhage
Bleeding inside the brain
Causes
o Mutation of MYH9 geneo Malignant hypertensiono Thrombotic thrombocytopenic
purpurao Schulman-Upshaw syndrome
Lab Diagnosis
Platelet Count and Morphology
o Degree of thrombocytopenia varies
o Platelet count is usually 40-80 X 109/L (Normal Value 150-450 X 109/L)
o Characterized by macrothrombocyte - Platelets are enlarged 15-20 µm in diameter (Normal size 1-4 µm)
o Mean platelet volume 30 fL (Normal Value 6.8-10.2 fL)
Clinical Features of MYH9 -RelatedThrombocytopenias
Condition Macrothrombocytopenia
Granulocyteinclusions
Nephritis andDeafness Cataracts
MHA Yes Linear Döhle No No
Epsteinsyndrome
Yes Absent orfaint
Yes No
Fechtnersyndrome
Yes Sphericalgranules
Yes Yes
Sebastiansyndrome
Yes Sphericalgranules
No No
Wright Stain
Döhle bodies
1.Neutrophils (most commonly seen)2.monocytes3.eosinophils4.basophils
Döhle bodies and Macrothrombocyte
Döhle bodies and Macrothrombocyte
Döhle bodies (Eosinophil)
Electron Microscopyo Increased amount of disorganized
microtubule
Immunocytochemistry
o Detectection ofNMMHCIIA complexes within theleukocytes
- Confirmatory test
Treatment
o Specific treatment is not requiredo In rare patients with severe bleeding,
platelet transfusion may be required
Complication - bleeding risk is increased by taking
drugs that decrease plateletfunction
e.g. Aspirin and NSAIDs
Questions:1. Mutation of what gene will result to
MHA?a. MYJ9 b. MZH9c. MYH9 d. MXH9
2. Other name for MHA?a. Dohle leukocyte inclusions with small plateletsb. Dohle leukocyte inclusions with giant leukocytesc. Dohle leukocyte inclusions with giant rbcd. Dohle leukocyte bodies with giant platelets
3. What are the 2 most common site ofbleeding in MHA?
a. mouth and nose b. mouth and skinc. nose and skin d. skin and brain
4. What inclusion bodies is commonly seen inMHA?
a. Heinz bodies b. Döhle bodiesc. Cabot ring d. Siderotic granules
5. What platelet morphologycharacterized MHA?
a.Microthrombocytesb.Macrothrombocytesc.Microleukocytesd.Macroleukocytes
PELGER-HUETPELGER-HUETANOMALYANOMALY
Mangon, Kimberly Christine L.Santos, Czarinnah F.
Vergara, Verlyn C.
• PHA is a benign dominantly inheriteddefect of terminal neutrophil differentiationsecondary to mutations in the lamin Breceptor (LBR) gene.
• Pelger, a Dutch hematologist, describedleukocytes with dumbbell-shaped bilobednuclei, a reduced number of nuclearsegments, and coarse clumping of thenuclear chromatin.
• Huet, a pediatrician, identified it as aninherited disorder.
• Genome-wide analysis of individuals fromthe Gelenau region of Germany was usedto identify the affected gene in humansas LBR gene, located on subband 1q42.1
• Heterozygotes have neutrophils with apredominance of bilobed dumbbell-shaped nuclei, which are also describedas pince-nez (ie, looking like pinched-nose spectacles)
• LBR also interacts with HP-1heterochromatin proteins
• LBR abnormalities do not affectneutrophil function
• Distinguishing this autosomal dominantdisorder from acquired orpseudo–Pelger-Huët anomaly isimportant
• Homozygous individuals are rare• In Homozygous individuals:
– Neutrophils contain a single, round,eccentric nuclei with clumped chromatinand little or no nuclear segmentation
– Basophils, eosinophils, andmegakaryocytes also show densenuclear chromatin and rounded nuclearlobes
• Unique physical findings are notobserved in heterozygousindividuals with Pelger-Huëtanomaly
• Homozygous individualsinconsistently have skeletalanomalies such as postaxialpolydactyly, short metacarpals,short upper limbs, short stature,or hyperkyphosis.
MORTALITY/MORBIDITY
• Neutrophilic function is normal• HETEROZYGOUS:
– are in good health– natural resistance to infection is unimpaired
• HOMOZYGOUS:– Skeletal anomalies– Developmental delay– Seizures
• From Switzerland,Germany, or Holland
• In ALL ethnic groups- Whites, Blacks and Asians
• Male-to-female ratio is 1:1• May also be in individuals of all ages
• Distinguished from:Acquired or pseudo–Pelger-Huët
anomaly• observed in individuals with myeloid
leukemia, myelodysplasia, and bi-lineage acute lymphocytic leukemia
Acquired or pseudo–Pelger-Huëtanomaly
– in the course of acute or chronicmyelogenous leukemia and inmyelodysplastic syndromes
– cells tend to appear late in the disease– morphologic changes have been
described in myxedema
• MYXEDEMA– Panhypopituitarism– Vitamin B-12 and folate deficiency– Multiple myeloma– Enteroviral infections– Malaria– Muscular dystrophy– Drug sensitivity
In Acquired or pseudo–PHA:– Fewer bilobed cells– Higher percentage of normal trilobed
neutrophils– Presence of leukemic and immature cells
*predicative of the clinical onset of myelodysplastic disorders andmalignant conditions.
• Heterozygous PBS– neutrophils are bilobed, spectacle-shaped nuclei -
> pince-nez– Cells with twin, joined, and plump nuclei
resembling dumbbells are predominant– A thin bridge joins the two lobes– 69-93% of the neutrophils show nuclear
segmentation that is arrested at the bilobe level– neutrophils that possess a nonlobulated oblong
or peanut-shaped nucleus is often present– >10% of cells contain 3 lobes; 4 lobes are rare
• Homozygous PBS– neutrophils with a single, round, eccentric
nucleus (clumped chromatin and little or nonuclear segmentation)
– most neutrophils are round or oval– basophils, eosinophils, and megakaryocytes
show dense nuclear chromatin and roundednuclear lobes
– bone marrow: normal morphologic features inthe myeloid precursors to the myelocyte stage
• Electron microscopy: persistence ofnucleoli in the mature neutrophils with asingle oval nucleus -> altered andretarded nuclear maturation of themyeloid precursors
• No treatment is needed
• have good health• natural resistance to infection is
unimpaired
-END
Questions:• What is the treatment for Pelger-Huët anomaly?a. Corticosteroids b. Splenectomy c. Platelet transfusion
d. none
• Describe the nucleus of the neutrophil in heterozygous Pelger-Huëtanomaly.
a. spectacle-shape b. Single c. Eccentric d. bilobed, oval
• What is the gene affected in Pelger-Huët anomaly?a. DAF b. LBR c. MYH9 d. PIGA
• Heterozygotes have neutrophils with a predominance of bilobeddumbbell-shaped nuclei which are also described as what?
a. Pince-nez b. Rosette c. Oval d. Irregular
• The following are findings in homozygous Pelger-Huet EXCEPT:a. postaxial polydactyly b. short stature c.
Hyperkyphosis d. resistance to infection
ANSWERS
• D• A• B• A• D
Dohle Bodies• first described by H. Dohle in 1911 in
patients with scarlet fever
• remnants of free ribosomes or rough-
surfaced endoplasmic reticulum
Morphology
• small, oval inclusions in the peripheral
cytoplasm of polymorphonuclear
neutrophils
• stain pale blue with Wright stain
Dohle Bodies• are considered normal if they are
present only in small numbers
• If there are many neutrophils inthe bloodstream containing Döhlebodies, these can be referred toas toxic neutrophil.
Dohle Bodies• They are found in:
– Infective and inflammatory states
– severe burns
– Tuberculosis
– post chemotherapy
– pregnancy
Dohle Bodies
• More abundant in cats andhorses
Vacuoles• Vacuoles are vacuoles
• vacuoles appear as holes in thecytoplasm and are frequentlyfound in association with toxicgranulation.
• They are form by the ingestionand degradation of bacteria andare unevenly distributed.
•
Vacuoles• The occasional tiny single
"vacuole" present in thecytoplasm of one or twolymphocytes is always NOTsignificant.
• On the other hand, they areClinically significant whenassociated with toxicgranulation, degranulation orDohle bodies
Vacuoles• Found in
– Infection and Toxic effect of
ethanol.
– They are also found in Jordan's
anomaly
WHITE BLOODCELL
INCLUSIONBODIESBy: Elizes, Nicole Joy B.
Toxic granulationRefers to changes in granulocyte cells
seen on examination of theperipheral blood film of patients withinflammatory conditions.
Toxic granulations are abnormally large,dark coarse granules found ingranulocytes, particularly neutrophils.
Toxic Granulation• Morphology:
Increased granulation. Granulation ismore basophilic and larger thannormal.
• Found in:- Severe bacterial infection- Normal pregnancy- G-CSF and GM-CSF Therapy
- Patients with sepsis
Drumstick Represent the inactive X chromosome
of the female. The presence andfrequency of drumstick is related tothe number of X chromosome.
They do not occur in normal males, inindividuals with the testicularfeminization syndrome who arephenotypically female but genetically(XY) male, or in Turner’s syndrome(XO) females.
DrumstickMorphology:
Drumstick shaped nuclearappendage. ± 1.5 µm in diameter andattached to the nucleus by a filament.
Found in:- Neutrophils of females- Males with Klinefelter syndrome
Sessile Nodule• Morphology:
Inactive X chromosome found asnodule on neutrophils of females.
• Found in:- Neutrophils of females
Detached nuclearfragments
• Morphology:Detached nuclear material in cytoplasm.
• Found in: - Dysplastic granulopoiesis due to HIVinfection- Patients on anti cancer chemotherapy- Administraion of drug interfering withDNA synthesis, including chlorambucil,mycophenolate, mofetil and tacrolimus
Actin Inclusion• Found in: - Congenital abnormality associated
with anemia and grey skin
Large Granular Lymphocyte
• Morphology:Small eosinophilic granules in thecytoplasm of large lymphocytes
• Found in:Natural killer cellsLymphokine activated T cells
Mott Cells
• Morphology:Plasmacytoid lymphocyte with globularinclusions composed of immunoglobulin.
• Found in:Reactive changes in peripheral blood
Auer Rods• Morphology:
Small azurophil rods in the cytoplasm ofmyeloblasts and promyelocytes.
• Needle-shaped, pink-staining inclusion in thecytoplasm
• These inclusions contain enzymes such as acidphosphatase, peroxidase, and esterase and mayrepresent abnormal derivatives of cytoplasmicgranules.
Found in:Acute myeloblastic leukemiaMyelodysplastic syndromes
• The End..
Questions
• 1. These are plasmacytoid lymphocyte withglobular inclusions composed ofimmunoglobulin.
• A. large Granular lymphocyte• B. Auer Rod• C. Mott Cells• D. None• 2. What disease can be found in Large
granular lymphocyte?• A. Natural killer cells• B. Lymphokine activated T cells• C. Both• D. None
• 3. A needle-shaped, pink-staining inclusion inthe cytoplasm of myeloblasts andpromyelocytes containing azurophil rods.
• A. Auer Rods• B. Mott Cell• C. Large Granular Lymphocyte• D. None• 4. What disease can be found in mott cell?• A. chronic LGL lymphocytosis• B. Reactive changes in peripheral blood• C. aggressive LGL leukemia• D. None
• 5. These inclusions contain enzymes thatmay represent abnormal derivatives ofcytoplasmic granules.
• A. Acid Phosphatase• B. Peroxidase• C. Esterase• D. All the above
QUESTIONS
QUESTIONS:
1. In what condition/s can you find toxicgranulation?
A. Severe bacterial infectionB. Patients with sepsisC. HIVD. Both a and bE. Both b and c
QUESTIONS:
2. It refers to changes in granulocyte cellsseen on examination of theperipheral blood film of patients withinflammatory conditions?
A. InfectionB. SepsisC. Toxic granulationD. None of the above
QUESTIONS:
3. Which of the following findings inthe cytoplasm of granulocytes issuggestive of an inflammatory process ?
A. Toxic granulationB. Dohle bodiesC. Cytosolic vacuolationD. All of the above
QUESTIONS:
4. In what particular white blood cell canyou find toxic granulations?
A. EosinophilB. BasophilC. LymphocyteD. Neutrophil
QUESTIONS:
5. Which of the following inclusion bodiesare found in neutrophils of female?
A. DrumstickB. Detached nuclear fragmentsC. Sessile noduleD. Both a and bE. Both a and c
Questions• Give at least 3 condition where you
can find your Dohle bodies• This is a familial disorder in which
vacuoles are present in the cytoplasmof granulocytes, lymphocytes, andmonocytes.
• In relation to the formation ofvacuoles, this is often seen withprolonged exposure to drugs such asantimicrobial agents and alcohol orradiation.
CHRONIC MYELOCYTICCHRONIC MYELOCYTICLEUKEMIA(CML)LEUKEMIA(CML)
Maglanque, Carolina G.#18
CHRONIC MYELOCYTIC LEUKEMIA (CML)CHRONIC MYELOCYTIC LEUKEMIA (CML)•Chronic Granulocytic Leukemia (CGL).•Form of leukemia characterized by the increasedand unregulated growth of predominantly myeloidcells in the bone marrow and blood.•Resistance to apoptosis, abnormal signaling andadhesion.•9;22 chromosomal translocation(Philadelphiachromosome)•Peak age of 30-50.
EpidemiologyEpidemiology Exposure to ionizing radiation
Example:-People exposed to the atomic
bombings of Hiroshima• Philadelphia chromosome
Philadelphia chromosomePhiladelphia chromosome
Signs and SymptomsSigns and Symptoms Enlarged spleen Malaise, low-grade fever Gout Increase susceptibility to infection Anemia Thrombocytopenia with easy bruising Night sweats
DiagnosisDiagnosisComplete Blood CountPeripheral Blood Increase granulocytes of all types Normal or decrease erythrocytes Normal reticulocytes Presence of nucleated RBCs Normal or increase platelets LAP is decrease(<13)
DiagnosisDiagnosisB. Bone marrow aspiration and biopsy
Bone Marrow in CMLBone Marrow in CML
Bone Marrow in CMLBone Marrow in CML
DiagnosisDiagnosisC. Fluorescent In Situ
Hybridization(FISH) Philadelphia chromosome
- BCR/ABL fusion gene-TRITC (red) for BCR on ch 22, FITC (green) forABL on ch 9-If the BCR/ABL fusion gene is present, aYELLOWYELLOW fusion signal will appear
ClassificationClassificationChronic phase
- few blast in the blood and bonemarrow.- 3-4 years(without therapy)
ClassificationClassification Accelerated phase
- more blast in the blood and bonemarrow; fewer normal cells.-fatal within months
WHO criteria: 10–19% myeloblasts in the blood or bone marrow >20% basophils in the blood or bone marrow Platelets count <100,000, unrelated to therapy Platelet count >1,000,000, unresponsive to therapy Cytogenetic evolution with new abnormalities in addition to
the Philadelphia chromosome Increasing splenomegaly or white blood cell count,
unresponsive to therapy
ClassificationClassification Blast crisis
- terminal phase and clinically behaveslike an acute leukemia.- more than 30% of the cells in theblood or bone marrow are blast cells.- fatal within weeks.
Criteria: >20% myeloblasts or lymphoblasts in the blood or bone
marrow Large clusters of blasts in the bone marrow on biopsy Development of a chloroma (solid focus of leukemia outside
the bone marrow)
TreatmentTreatment Targeted therapy
- tyrosine kinase inhibitors Imatinib mesylate (Gleevac or Glivec)
- first line therapy Dasatinib ( Spyrcel)
-TK inhibitor that blocks several oncogenicproteins
Nilotinib ( Tasigna)-bind more tightly than imatinib to the Bcr-Ablabnormal fusion
Omacetaxine-administered subcutaneously .
Ponatinib-oral drug
TreatmentTreatmentChemotherapy
- stops the growth of the cell Hydroxyurea ( Hydrea)Stem cell transplant
- for patient who developed T315Imutation
TreatmentTreatmentSurgery Splenectomy
Biologic therapy/ Immunotherapy- uses the patient’s system to fightcancer.
PrognosisPrognosisDepends on the following: The patient’s age. The phase of CML. The amount of blasts in the blood or
bone marrow. The size of the spleen at diagnosis. The patient’s general health.Lowest risk group: 98 monthsMiddle group: 65 monthsHighest risk group: 42 months
Questions:
Questions:Questions: Philadelphia chromosome is characterized
by which translocation?A. 19;22 B. 9;22 C. 9;12
D.19;12 In CBC, what is the common findings for
granulocytes?A. Increase B. Decrease C.
Normal D. Absent Level of Leukocyte alkaline phosphatase in
CML.A. Increase B. Decrease C. Normal Classsified as terminal phase in CML. Chronic B. Accelerated C. Blastic D.
Refractory Stage of CML which is fatal within months.
A. Chronic B. Accelerated C. Blastic D.Refractory
Prepared by :Alejandro, Louie Carmela KimPutong, Ma. Fatima B.Mendoza, Maria Lady Lyn
ACUTE LEUKEMIAACUTE LEUKEMIA
Is a result of malignant transformation of a stem cell leading tounregulated proliferation and arrest in maturation at theprimitive blast stage.
Acute leukemia is a form of cancer that affects the white bloodcells. It can present in many forms such as Acute LymphocyticLeukemia (ALL), which is very common in children,especially 2-5 years of age; and Acute Myelogenic Leukemia(AML).
See video
ACUTE LEUKEMIA SUMMARY
Age : all ages (young and old)
Clinical onset : sudden
Course (untreated) : 6 months or less
Leukemic cells : immature >30% blasts
Anemia : prominent
Thrombocytopenia : prominent
WBC count : variable
Lymphadenopathy : mild
Splenomegaly : mild
Symptoms
low fever, anemia, pale skin, general ill feeling, easily bruised skin, and/or frequent nose bleedsor bleeding gums.
abdominal pain with an enlarged spleen, and infections with sores in the mouth.
Causes
unknown, but risk of contracting the disease increases with a family history, Down Syndrome,or other congenital disorders, identical twins, or exposure to toxic chemicals.
Diagnosis
The first indication of a problem is typically an observation of theaforementioned symptoms.
A physical exam with studies of the blood, bone marrow, or cerebral spinalfluid should follow to confirm the diagnosis.
In some cases certain x-rays or CT scans may also be used to confirm thediagnosis.
Treatment
blood or platelet transfusions, anticancer medication and radiation treatments. A bone marrow transplant may be necessary in some cases. A physician may
also prescribe cortisone drugs and pain relievers (except aspirin) to help apatient deal with symptoms.
Laboratory diagnosis:Laboratory diagnosis:
Increased number of immature cells in the bone marrow including blast,promeolocytes , promonocytes
The term used to described the coexistence of immature and mature cell formsis “hiatus leucaemicus”
Identification of the cell lineage of the leukemic cells.
Peripheral blood:Peripheral blood: Anemia- normocytic,normochromic Decreased platelets Variable WBC count
Classification of the degree of peripheralinvolvement: Leukemic- increased WBC due to blast Subleukemic- blast without increased WBC Aleukemic- decreased WBC with no blast.
Acute Lymphoblastic leukemiaAcute Lymphoblastic leukemia
Is primarily a disease of childhood (2 and 10years) and rare in adult
is a form of leukemia, or cancer of the whiteblood cells characterized by excess lymphoblast
Malignant, immature white blood cellscontinuously multiply and are overproduced inthe bone marrow
causes damage and death by crowding outnormal cells in the bone marrow, and byspreading to other organs
Signs and symphtomsSigns and symphtoms fatigue, pallor, fever, weight loss, irritability, anorexia, infection, bleeding, and bone pain
Types of ALL Most common cellL1 children • small with fine or
clumpedhomogenous nuclearchromatin
• absent or indistinctnucleoli
L2 adult • large andheterogenous withvariable nuclearchromatin andprominent nucleoli
• nucleus is irregularL3 is a very rare
form of ALL
• is large, with fine,homogenous nuclearchromatin containingprominent nucleoli
• nucleus is regularoval to round
Age , WBC count and cell type(mostimp.)
Chromosomal translocation- thestrongest predictor of adverse treatmentoutcome for children and adult
Philadelphia chromosome(t(9;22))-is anindicator of adverse effects
(t(9;21))-marker in childhood with ALLpatient
Early pre-B cell(most commonpresence of surface immunoglobulin)
Mature pre-B cell( presence ofcytoplasmic immunoglobulin)
B cell T cell
DiagnosisDiagnosis complete blood count blood smears bone marrow biopsy
TREATMENTTREATMENT Methotrexate Chemotherapy radiation therapy
QuestionsQuestions How can you differentiate the
immature pre-B cell from mature pre-B cell?
a)Presence of surface immunoglobulinb)Presence of cytoplasmic
immunoglobulinc)Bothd)Neither
How can you differentiate the maturepre-B cell from immature pre-B cell?
a)Presence of surface immunoglobulinb)Presence of cytoplasmic
immunoglobulinc)Bothd)Neither
What is the most common treatmentfor ALL?
a)Chemotherapyb)Radiotherapyc)Methotrexated)Aspirin
What is the strongest predictor ofadverse treatment outcome forchildren and adult?
a)Philadelphia chromosomeb)(t(9;21))c)Chromosomal translocationd)A and be)A and c
ACUTE MYELOIDACUTE MYELOIDLEUKEMIALEUKEMIA
(AML)(AML)
Prepared by : Putong, Ma Fatima B.Prepared by : Putong, Ma Fatima B.MT0831MT0831
Acute myeloid leukemia• Acute myeloid leukemia (AML) is one of four types of
leukemia.• The most common family of leukemia in children younger
than 1 year of age. It is rare in older children andadolescents, but a second incidence peak occurs at 40 yearsof age.
• AML is cancer of the blood-forming tissue (bone marrow).• Normal bone marrow produces red cells, white cells, and
platelets.• AML causes bone marrow to produce too many immature
white blood cells (blast cells).• See Video
Acute Myeloid LeukemiaSee Video
Acute myeloid leukemia• Suppresses normal blood cell production.
– Anemia, leucopenia, thrombocytopenia– Acute in which the onset is usually rapid, the
disease is very aggressive, and the cells involvedare usually poorly differentiated with many blasts.
• characterized by clonal proliferation ofmyeloid precursor cells with reduced capacityto differentiate into more mature cellularelements.
• results in accumulation of leukemic forms inbone marrow, peripheral blood, and othertissues.
ACUTE MYELOIDLEUKEMIA
--the myeloblast is alarge blast with amoderate amount ofcytoplasm, fine laceychromatin, andprominent nucleoli;10-40% ofmyeloblasts containAuer rods
Myeloblasts with Auer Rod
Classification of Acute Myeloid LeukemiasAML withRecurrentAbnormal
Karyotypes
AML withDysplasia
AML as a resultof previous
therapy-relatedMyelodysplasias
AML nototherwise
Categorized
Acute Leukemiaof Ambigiuos
Lineage
•AML witht(8;21)(q22;q22)
•AML with inv(16) 9p13q22)or t(16;16)(p13;q22)
•AML witht(15;17)(q22;q12) (APL)
•AML with11q23
•AML occurringafter a diagnosisof amyeloproliferativeormyelodysplasticdisease
•AML withhistory ofalkylatingagent exposure
•AML withtopoisomeraseexposure
•AML withotherexposuressuch asradiation
•AML with minimallydifferentiated
•AML withoutmaturation
•Acutemyelomonocyticleukemia
•Acutemonobalstic/monocytic leukemia
•Acute erythroidleukemia
•AcuteMegakaryocyticLeukemia
•Acute BasophilicLeukemia
•Acutebilineageleukemia
•Acutebiphenotypicleukemia
FAB Classification (Summary)M0: minimally differentiatedM1: without maturationM2: with maturation.M3: promyelocyticM4: myelomonocyticM5: monoblasticM6: erythroleukemiaM7: megakaryoblastic
ACUTE MYELOID LEUKEMIA(M0)
M0•Minimally differentiatedAuer Rods (absent)•No cell maturation•Negative in :
MyeloperoxidaseSudan Black B
ACUTE MYELOID LEUKEMIA(M1)
M1•“Myeloblastic without maturation”
•The bone marrow shows ≥ 90% blasts and < 10% promyelocytes•The disease occurs in older adults•Blasts same with M0•Auer rods (usually Positive) for MYELOPEROXIDASE orSUDAN BLACK B dye.•No specific recurrent chromosome abnormalities
MYELOBALSTIC WITH MATURATION
M2
•“Myeloblastic with maturation”
•The bone marrow shows 30-89% blasts and > 10%promyelocytes;•Auer rods and other aspects are present•Monocytic line –increased•It has a less favorable prognosis
ACUTE PROMYELOCUTIC LEUKEMIA (M3)
M3•“Hyper granular Promyelocytic”
•This form of AML has a bone marrow with >30% blasts•Is more virulent than other forms•Occurs with a medium age of 39•WBC count – decreased (low)•Treatment causes a release of the granules and may send the patient intodisseminated intravascular coagulation and subsequent bleeding
M3m – Hypogranular Promyelocytic
ACUTE MYELOMONOCYTIC LEUKEMIA (M4)
M4
•“Acute Myelomonoblastic Leukemia”
•Both myeloblasts and monoblasts are seen in the bonemarrow and peripheral blood•Infiltration of extramedullary sites is more commonthan with the pure granulocytic variants•WBC –elevated•Monocytic cells constitute atleast 20% of all marrowcells.
ACUTE MONOCYTIC LEUKEMIA (M5)
M5• “Acute Monoblastic Leukemia”
• >80% of the nonerythroid cells in the bone marrow aremonocytic•There is extensive infiltration of the gums, CNS, lymph nodesand extramedullary sites•This form is further divided into•M5A - Poorly differentiated (>80% monoblasts)•M5B - Well differentiated (<80% monoblasts)
ERYTHROLEUKEMIA (M6)
M6•“Erythroleukemia”
•Di Guglielmo’s Syndrome•This is rare and is characterized by a bone marrow having a predominance oferythroblasts•It has 3 sequentially morphologically defined phases;•Preponderance of abnormal erythroblasts•Erythroleukemia – there is an increase in both erythroblasts and myeloblasts•Myeloblastic leukemia – M1, M2, or M4•Anemia is common
ACUTE MEGAKARYOBASTIC LEUKEMIA (M7)
M7
Signs and Symptoms•• AnemiaAnemiaweakness and easy fatigue•• NeutropeniaNeutropeniainfections•• ThrombocytopeniaThrombocytopeniagingival bleeding, ecchymoses, epistaxis, menorrhagia
These three give rise to clinical findings :• Pallor• Fatigue• Shortness of breath on exertion• Easy bruising• Petechiae• Bleeding in the nose or from the gums• Prolonged bleeding from minor cuts• Recurrent minor infections or poor healing of minor cuts• Loss of appetite or weight loss• Mild fever
Treatments for AMLThere are four general types of therapy
ChemotherapyPhase One – Remission induction therapyPhase Two – Remission continuation therapy
Bone marrow transplant Radiotherapy Immunotherapy
Prognosis for AML• Survival rates greatly improved over past 25 years.• Remission rates inversely related to age.• Dependent upon several factors.
– Age– White blood cell count– Presence of translocations in bone marrow
QUESTIONS
1. What FAB classification where monocyticline increases?
a. M2b. M3c. M4d. M1
• 2. What FAB classification is associated w/t(16;16) or inv(16)(p13q22)?
a.M4b.M3c.M2d.M1
3.What do you call the large blast with amoderate amount of cytoplasm, fine laceychromatin, and prominent nucleoli whichcontains 10-40% Auer rods in AML?
a. Promyeloblastb.Myeloblastc. Promonoblastd.Prokaryoblast
4.What form of AML has a bone marrow with>30% blasts and it is more virulent than otherforms?
a. M3b. M4c. M5d. M2
5. What form of AML wherein infiltration ofextra medullary sites is more common than withthe pure granulocytic variants?
a.M4b.M3c.M5d.M2
Chronic LymphocyticLeukemia
CLL/ Chronic Lymphoid Leukemia
# 24Ong, TanyaYuinMT0831Dr. Asilo
Understanding CLL• Chronic lymphocytic leukemia (CLL) is one of the four
main types of leukemia.• Common in people 60 years and older.• Children do not get CLL.• CLL is the most common type of leukemia in North
America and Europe.• It is characterized by accumulation of small lymphoid
cells in the peripheral blood, bone marrow, & lymphoidorgans.
• They are derived from recirculating CD 5+, IgM+, IgD+B cells which are normally present in the peripheralblood
• CLL has a peripheral blood (lymphocytosis > 10 x 10⁹/ L)
• CLL starts with a change (mutation) to theDNA of a single cell called a lymphocyte.
• The change occurs in a B lymphocyte but othercells transforming from normal to leukemicmay have features of a T lymphocyte or a NKcell.
• Over time, the CLL cells multiply and replacenormal lymphocytes in the marrow and lymphnodes.
• Presence of “Smudge Cells” or bare nuclei canbe frequently found.
CommonTargetCell ofCLL
Othertarget cells
Healthy NormalLymphocytes
Chronic LymphocyticLeukemia Cells
Symptoms and Signs• CLL signs and symptoms usually develop
slowly.• No known cause of CLL.• Some people with CLL do not even have any
symptoms.• Many of the signs and symptoms of CLL are
more likely to be caused by other illnesses.• Specific blood tests and bone marrow tests
are needed to make a diagnosis.
Some signs and symptoms ofCLL include :
• Tiring more easily. People mayhave less energy due to fewerhealthy red cells and more CLLcells.
• Shortness of breath duringnormal activities. This is due tofewer healthy red cells andmore CLL cells.
• Swollen lymph nodes or spleen.High numbers of CLL cells cangather in the lymph nodes orspleen as the number of
CLL cells grows.
• Infections. People with a very high numberof CLL cells building up in the marrow mayhave repeated infections of the skin orother parts of the body.
• Weight Loss. Some people with CLL loseweight because they eat less and/orbecause they are using more energy.
*Some patients may also have othersymptoms, such as aches, fever
or night sweats.
Prognosis• Late stage patients usually have a more progressive
disease.• Significant subset of early stage eventually progress by --refractory to treatment --infectious Complications --autoimmune complications• Stage Definition 0 Absolute lymphocytosis >15 x 109/L. 1 Stage 0 + enlarged lymph nodes. 11 Stage 0 + liver or/and spleen ↑ ±
adenopathy. 111 Stage 0 + anemia ±organomegally or
adenopathy. 1V Stage 0 + thrombocytopenia ±
organomegally or adenopathy.
Notes to consider:• Average survival of the patient is 5 years but may
take an aggressive course with only 1-2 years ofsurvival.
• CLL is a Highly Variable disorder.• Not associated with radiation/ exposure to
occupational hazard.• Has the strongest tendency for familial incidence.• May results to altered humoral immunity resulting
from suppression of all classes ofimmunoglobulins, leading tohypogammaglobulinemia.
• May develop autoimmune disorders and produceautoantibodies to neutrophils, platelets, or RBCs(AIHA)
READY??READY????
Question # 1
1.) What do you call a “ Bare Nuclei” ?
A. Smudge Cells B. Vacuoles C. Pelger-Huet Cells D.Dohle Bodies
Question # 2
2.) What is the average survival of apatient with CLL?
A. 10 years B. 15 years C. 5 years D.2 years
Question # 3
3.) The most common target cell of theChronic Lymphocytic Leukemia.
A. T-Cell B. B-Cell C. NaturalKiller CellD. Lymphocyte Progenitor Cells
Question # 4
4.) Where is CLL most commonlyfound?
A. Africa B. Southeast Asia C. North AmericaD. India
Question # 5
5.) Which of the following is not a Sign& Symptoms of a CLL?
A. Anorexia B. NightSweatC. Swollen Lymph Nodes D. Fever
Hodgkin’s DiseaseBalasta, DarwinBasa, AaronnGiorla, Jake
∗ Hodgkin's lymphoma is a malignant disordercharacterized by painless, progressive enlargement oflymphoid tissue, usually first evident in cervical lymphnodes. Characterized by splenomegaly and thepresence of Reed-Sternberg cells in lymphoid tissue.
∗ The nomenclature of HL, formerly called Hodgkin'sdisease, is little changed from that of the Ryeconference.
∗ The hallmark of HL is the Hodgkin Reed–Sternberg(HRS vs. RS) cell.
∗ Accurate diagnosis and staging are critically importantfor successful treatment.
∗ Clinical staging provides strong predictor of prognosisand selection of a specific treatment regimen
Hodgkin's Lymphoma
∗ treatment of Hodgkin's disease is based on solidprinciples of radiobiology and chemotherapy thatserve as a model for all other treatment regimens(treatment has become very successful).
∗ untreated, 90% of patients with Hodgkin's disease diewithin 2-3 years. 80% or more are now curable withmodern therapy.
∗ one of the best examples of a malignancy that can becured if diagnosed and managed well
∗ Its cause remains unknown.
∗ Hodgkin's disease usually presents as anenlargement of the lymphoid organs,frequently accompanied by systemic symptomssuch as∗ fever∗ weight loss∗ Fatigue
∗ unique in several respects.∗ Unlike the non-Hodgkin's lymphomas, the
tumor masses∗ largely comprise normal reactive T cells∗ usually CD4 predominant, not a clone of
malignant lymphocytes.
DIAGNOSIS &CLASSIFICATION
∗ Reed-Sternberg cell - which is a largebinucleated, multinucleated or mononuclear(Hodgkin) cell with each nucleus bearing a verylarge inclusion-like nucleolus∗ closely resembles a macrophage-like cell than a
lymphocyte.∗ Immunophenotyping studies : monoclonal B cells
derived from germinal center cells∗ These neoplastic cells appear in an
immunoproliferative background containingvariable numbers of lymphocytes, histiocytes,eosinophils and plasma cells∗ Relative number may vary from very high to very
low, but always make up < 2% of the apparenttumor load.
∗ difficult to study because they are present in smallnumbers and are difficult to separate from thesurrounding infiltrate of reactive cells.
∗ mechanism and their precise role in the malignantprocess remain obscure
REED-STERNBERG CELLS &LYMPHOCYTIC/HISTIOCYTIC
CELLS
Reed-Sternberg cell in a marrow smear(Wright's stain), showing the mirror nucleiwith prominent nucleoli.
Lymph node section from a patient withHodgkin's disease, showing a classic Reed-Sternberg cell
- Lymphocyte-Predominant Hodgkin Lymphoma- Classical Hodgkin Lymphoma
Type of Hodgkin’s Disease
Lymphocyte-Predominant HodgkinLymphoma
Is the least common form of HD and accounts for fewerthan 1% of all HD cases. The disease affects moremen than women, and it tends to occur in individualswho are older, HIV-positive, or residents of non-industrialized nations. The disease usually arises in thelymph nodes of the abdomen and pelvis (hip region),while sparing the nodes of the neck and underarms.LDHD is an aggressive form of HD, and most patientsare diagnosed with advanced-stage disease.
Divided into two subtypes:- Nodular Lymphocyte-Predominant Hodgkin lymphoma- Diffuse lymphocyte-Predominant Hodgkin Lymphoma
Nodular Lymphocyte- Predominant Hodgkinlymphoma
∗ Nodular lymphocyte predominant Hodgkin's disease(nLPHD) accounts for about 5% of all HD cases. It is threetimes more common in men than in women, and it primarilyaffects young adults in their third through fifth decades of life.Most patients (75%) are diagnosed at an early stage (e.g.,Stage 1), and a majority (by some reports up to 90%) respond totherapy with a complete response. The peripheral lymph nodes(underarm, neck, ear, and groin nodes) are frequently involved,whereas the deep, intrathoracic (within the trunk) nodes arespared.
∗ Classic Reed-Sternberg cells are not seen or are veryuncommon in patients' tissue samples. Instead, large, circularmeshworks of cells take over the lymph nodes. These nodulescontain unusual lymphocytes and histiocytes known as "L & Hcells" or "popcorn cells," as well as B-cells and scattered T-cells.The T-cells may be distributed in a nodular (knot-like)arrangement within the tissues.
∗ L & H (Popcorn) cells
∗ In its early stages, LPHD is characterized bylymphocytes that are mostly B-cells; however,in LPHD's later stages, T-cells may surpass B-cells in number. LPDH has a slow clinicalcourse. Late relapses are common, but theyusually do not affect survival; survival isfavorable even among patients with recurrentdisease. Patients with this diagnosis are morelikely than other HD patients to develop non-Hodgkin's lymphomas (NHLs), typically largecell lymphoma of B-cell type.
Diffuse Lymphocyte-PredominantHodgkin Lymphoma
∗ is an extremely rare form of Hodgkin'sdisease. It not as well defined as nLPHD.In dLPHD, there are no circular meshworksof cells, and B-cells are missing. Instead,the lymphatic tissue is dominated byspread out arranged T-cells.
Classical Hodgkin Lymphoma
∗ Comprises a group of heterogenous germinal centercell disorders
∗ Reed-Sternberg cells, large lymphoid cell with abilobed nucleus or two nuclei with prominenteosinophilic nucleoli and abundant cytoplasm, arethe diagnostic neoplastic cells
∗ Can be divided into four subtypes depending on thearchitectural features, composition of the reactivebackground, and relative proportion of neoplasticcells:
- Nodular Sclerosis Hodgkin’s disease - Mixed Cellularity Hodgkin’s disease - Lymphocyte Rich Hodgkin’s disease - Lymphocyte Depleted Hodgkin’s disease
Classical HodgkinSubtype Diagnostic Feature
Nodular Sclerosis Broad collagen bands with thickeningof the nodal capsule and lacunar cells
Mixed Cellularity
Reed-Sternberg cells are scatteredamong the diffuse backgroundproliferation of small lymphocytes,histiocytes, eosinophils, neutrophilsand plasma cells
Lymphocyte Rich Background cellularity is lessheterogenous
Lymphocyte DepletedScarcity of cells of reactivebackground, and neoplastic Reed-Sternberg cells
Nodular Sclerosis Hodgkin Lymphoma
Mixed Cellularity Classical Hodgkin Lymphoma
Lymphocyte Rich Hodgkin Disease
Lymphocyte Depleted Hodgkin Lymphoma
∗ most common presentation of a Hodgkin's disease patientis the appearance superficial lymph node or group ofnodes in a young adult.
∗ first appearance in a single node group a healthyindividual make it difficult to distinguish from thelymphadenopathy associated with an infectious process.
∗ Hodgkin's nodes can on occasion wax and wane in thesame way as those associated with an infectious process.
∗ The diagnosis is obviously easier when the mass is large,presents in more than one area, and is associated withsystemic symptoms (B symptoms) such as:∗ night sweats, fever, weight loss, pruritus, or fatigue.
CLINICAL FEATURES
∗ most common areas of involvement in young patients :∗ cervical, axillary, and mediastinal nodes
∗ incidence of Hodgkin's disease has been linked toseveral factors, including∗ environment, social status, infectious agents, and genetic
propensity.∗ slightly more common in men, occurred as clustered
cases in families, communities, and schools.∗ Patients who have had infectious mononucleosis or
have a positive test for prior EBV infection have athreefold increased risk for developing the disease.
∗ Accurate staging is extremely important∗ natural history of the disease suggests that it arises in a single site
and then spreads∗ primary objective of staging is to determine the current location of all
the disease in the patient in order to plan a treatment that willaddress each of the involved areas and all contiguous sites ofpossible spread.
STAGING
Staging System for Hodgkin’s DiseaseStage Description Example
I Involvement of a single lymphoid region or a singlenonlymphoid site (IE)
Nodes on one side of the neck only
II Involvement of two or more regions on the sameside of the diaphragm
Nodes in the neck and chest
III Involvement of two or more regions on both sidesof the diaphragm
Nodes in the neck and retroperitoneum orthe spleen
IV Spread of disease from lymphoid sites tononlymphoid organs, involvement of more than onenonlymphoid organ
Nodes in the chest and infiltration of themarrow and lung
B Each stage is further modified as B by thepresence of fever, weight loss, or night sweats
Nodes in the retroperitoneum and groin withfever and night sweats (IIB)
History & Physical Examination∗The history should document the timingand characteristics of the onset of thedisease and the presence of systemic (B)symptoms∗physical examination, all portions of thelymphoid organs should be carefullyexamined∗Special attention should be paid
∗ the oral pharynx (Waldeyer's ring), thepopliteal and epitrochlear regions, thesubclavicular regions, common axillary,anterior and posterior cervical, andinguinal regions.
Biopsy∗biopsy of the principal tumor mass oraccessible enlarged node should be done,and the results reviewed with anexperienced hematopathologist.
Radiologic Studies∗routine chest x-ray will reveal patients with bulky mediastinal disease∗computed tomography (CT) scan accurately detect lymph node involvement ofthe mediastinum and abdominal nodes∗bipedal lymphangiography can be performed to evaluate retroperitoneal nodesof the lower abdomen.∗magnetic resonance image (MRI)Laboratory Studies∗laboratory evaluation of the Hodgkin's disease patient should include a
∗ complete blood count, tests of renal and liver function(ALP, LDH), serum calcium,and bilateral iliac crest marrow aspirates and biopsies.
∗studies of iron supply if anemia is present∗Abnormalities of the granulocyte and lymphocyte counts.∗guided needle biopsy of the lesion or laparoscopic liver biopsy if abnormalliver chemistries or a suspicious lesion on CTTherapy∗both radiotherapy and chemotherapy can cure Hodgkin's disease
THANKS!! ^_^
NAVAL, RICA NELL A.#23
DE LEON, LYSANDER LINUS D.# 9
MULTIPLEMYELOMA
MULTIPLE MYELOMA is….
*neoplastic proliferation of plasma cells, primarilyoccurring in the bone marrow
*plasma cell cancer characterized bymonoclonal gammopathy and multifocaldestructive bone lesions throughout the skeleton* also called plasma cell myeloma or Kahler'sdisease
INCIDENCE rare under age 40 50-75 yrs. (peak of incidence.) mean age at the time of diagnosis is 62 years equal sex distribution second most prevalent blood cancer (10%)
after non-Hodgkin's lymphoma. 1% of all cancers and 2% of all cancer deaths
PATHOGENESIS Chromosomal and gene damages loss of
control on antibody production Clonal proliferation of malignant plasma cells –
BONE MARROW May synthesize complete Ig or an L-chain subunit
-IgG --- 50% of patients-IgA --- 25%
Decreased ability to synthesize normal Ig againstspecific ags
Chromosome 13,14 abnormalities --- 50%patients
SYMPTOMS Bone pain -- most common symptom Infection – most common cause of death Neurologic symptoms Renal failure – 50% of cases Anemia (NC,NC) Bleeding
Conditions associated with Mproteins
Stable production Monoclonal gammopathy of undetermined significance Smouldering multiple myeloma
Progressive production Multiple myeloma (IgG, IgA, free light chains, IgD, IgE) Plasma cell leukaemia; Solitary plasmacytoma of bone Extramedullary plasmacytoma Waldenström's macroglobulinaemia (IgM) Chronic lymphocytic leukaemia; Malignant lymphoma Primary amyloidosis Heavy chain disease
Non neoplastic conditions: Cirrhosis,Sarcoid,CaColon/Breast
Multiple Myeloma
LABORATORY FINDINGSPeripheral Blood Smear-normochromic, normocytic anemia-normoblasts may be present-leukocyte count is slightly decreased, normal, or slightlyincreased-platelet count is usually normal, but may be decreased
Most striking feature: marked degree of rouleau formation
Peripheral Blood Smear
LABORATORY FINDINGS
Bone marrow-presence of plasma cells or myeloma cells (less than 1% to over 90%)
Serum protein electrophoresis-shows an M-spot (homogeneous band in the gamma- or beta-region)-hypogammaglobulinemia (when only light chains are produced by theneoplastic plasma cells)
Immunoelectrophoresis-shows that monoclonal protein is:
*IgG in over half the cases*IgA in about one-fifth*IgD in less than 1%*IgE very rarely
Bone Marrow Aspirate (Normal)
Bone Marrow Aspirate (MM)
Bone Marrow Aspirate (MM)
LABORATORY FINDINGS-5% of myeloma proteins are cryoglobulins
(proteins that precipitate from cooled serum andredissolve on warming)
-Bence Jones protein-Myeloma kidney—due to excretion of light chains-Amyloidosis (10-15% of cases) -- may be a factor
in the renal failure.
LABORATORY FINDINGS Other Findings:-serum monoclonal immunoglobulin-radiologic evidence of lytic bone lesions
(osteoclastic activity, hypercalcemia andneurologic changes)
-Serum globulin is usually increased-elevated ESR
Laboratory DiagnosisHelpful Mnemonics:
•[C] Calcium elevation in the blood S.Calcium >10.5 mg/l or upper limit ofnormal{8.6-10 mg/l}•[R] Renal insufficiency S. Creatinine > 2mg/dl{0.6-1.3 mg/dl}•[A] Anemia Hemoglobin < 10 g/dl or 2 g <normal{12-18g/dl}•[B] Lytic bone lesions or osteoporosis
Lytic lesions(Punched out lesions) on XRay.
Vertebral collapse secondary toosteoporosis/pathological fracture
1.Normal Plasma 2.Polyclonal Hyperglobulinemia3.Monoclonal Spike4.Bence Jones proteins in urine
Bence Jones Protein
MULTIPLE MYELOMA
DIAGNOSTIC CRITERIA: ALL 3 REQUIRED
1.Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma
2.Monoclonal protein present in the serum and/or urine*
3.Myeloma-related organ dysfunction (1 or more)• [C] Calcium elevation• [R] Renal insufficiency• [A] Anemia Hemoglobin• [B] Bone lesions or osteoporosis
*Non-secretory Multiple myeloma
Differential Diagnosis
MGUS AsymptomaticMultiple Myeloma
Symptomatic MultipleMyeloma
Serum M protein <30 g/L Serum M protein >30 g/L M protein in the serumor urine
Clonal † bone marrowplasmacytosis <10%
Clonal bone marrowplasmacytosis >10%
Clonal bone marrowplasmacytosis orplasmacytoma
No other B celllymphoproliferativedisorder
No related organ andtissue impairment
Related organ andtissue impairment
No related organ andtissue impairment
STAGING International Staging System Durie-Salmon staging system
STAGINGInternational Staging System
Stage I: β2-microglobulin (β2M) < 3.5 mg/L,albumin >= 3.5 g/dL
Stage II: β2M < 3.5 mg/L and albumin <3.5 mg/dL; or β2M 3.5 mg/L - 5.5 mg/Lirrespective of the serum albumin
Stage III: β2M >= 5.5 mg/L
STAGINGDurie-Salmon staging system
Stage I: all of Hb > 10g/dL normal calcium Skeletal survey: normal or single plasmacytoma or
osteoporosis Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA Urinary light chain excretion < 4 g/24h
Stage II: fulfilling the criteria of neither I nor III Stage III: one or more of
Hb < 8.5g/dL high calcium > 12 mg/dL Skeletal survey: Three or more lytic bone lesions Serum paraprotein > 7g/dL if IgG, > 5 g/dL if IgA Urinary light chain excretion > 12g/24h
Stages I, II, and III of the Durie-Salmon stagingsystem can be divided into A or B depending onserum creatinine:
A: serum creatinine < 2 mg/dL (< 177 umol/L)B: serum creatinine > 2 mg/dL (> 177 umol/L)
PROGNOSIS 62 months for stage 1 disease 45 months for stage 2 disease 29 months for stage 3 disease.
Chromosome 13 abnormalities – POORPROGNOSIS
TREATMENT Initial therapy- depends on the patient’s age- high-dose chemotherapy with hematopoietic
stem-cell transplantation: patients under the age of65
- Autologous stem cell transplantation: thetransplantation of a patient’s own stem cells afterchemotherapy (most common type of stem celltransplantation for multiple myeloma)
- Allogeneic stem cell transplantation --transplantation of a healthy person’s stem cells intothe affected patient (available to a small percentageof patient)
- Patients over age 65 -- chemotherapy withmelphalan and prednisone
Thank you for listening
QUESTIONS
QUESTIONS1. All of the following are symptoms associated
with multiple myeloma EXCEPT…a. Weakness, Fatigueb. Spinal cord compressionc. Normocytic, hypochromic anemiad. Hypercalcemia
QUESTIONS2. Abnormalities with which chromosome is
associated with multiple myeloma with POORPROGNOSIS?a. Chormosome 15b. Chromosome 20c. Chromosome 13d. Chromosome 8
QUESTIONS3. Which of the following statements is TRUE
about multiple myeloma?a. MM is a neoplastic proliferation of plasmacells, primarily occurring in the bone marrowb. plasma cell cancer characterized by monoclonal gammopathy and multifocaldestructive bone lesions throughout the skeletonc. Eitherd. Neither
QUESTIONS4. Peak of incidence for multiple myeloma occurs
betweena. 0-10 years oldb. 20-30 years oldc. 50-75 years oldd. 35-40 years old
QUESTIONS
5. Another term for Multiple Myeloma is…a. plasma cell myelomab. Kahler’s diseasec. eitherd. neither
Questions1.) Cause of recurrent infection of a patient withmultiple myeloma
a.) neutropeniab.) Waldenström's macroglobulinaemiac.) renal impairmentd.) M protein
Questions2.) Which of the following is true in the diagnosisof Multiple Myeloma
a.) Serum M protein >30 g/Lb.) No related organ and tissue impairmentc.) Serum M protein <30 g/L
d.) Calcium elevation in the blood
Questions3.) What causes hypercalcemia in a patient withmultiple myeloma?
a.) neutropeniab.) renal impairmentc.) OFA secretion of Myeloma cellsd.) none of the above
Questions3.) Laboratory procedures done in the diagnosis ofmultiple myeloma:
a.) Blood chemistry: calcium determinationb.) Imaging testsc.) bothd.) neither
Questions4.) True or false: Multiple myeloma could be ruledout if there is an absence of M proteins in thepatients serum, even if the common symptoms arepresent.
Questions5.) What causes Lytic bone lesions in a patientwith multiple myeloma?
a.) Osteoblastsb.) Osteocytesc.) Bone Macrophagesd.) neither
NON- HODGKIN’S LYMPHOMA
Non-Hodgkin’s Lymphomas
non-Hodgkin's lymphomas (NHLs) are aheterogeneous group of disorders characterized bymalignant proliferation of B or T lymphocytes. Froma clinical standpoint, lymphomas generally presentas SOLID TUMORS of the lymphoid system
type of cancer that originates in a subset of whiteblood cells called lymphocytes. lymph nodes Spleen tonsils, thymus Lymphatic tissue
Hodgkin's vs. non-Hodgkin's lymphoma:What's the difference?
Hodgkin’sLymphoma
Non Hodgkin’slymphoma
-Less common -more common- Reed-Sternberg cell -no Reed-Sternberg
cell-Young people (20-30)Older people (55 andup)
-risk increases with age(60’s)
Reed-Sternberg cell
Simplified schema of Hematopoetic Cancers
Myeloid
Lymphoid
Acute and chronic
Myeloid‘Leukemias’
LymphomasHodgkins (30%)
Non Hodgkins(70%)
WBC
RBC
Platelets
B Cells
T cells
NHL: Epidemiology
85% are B cell type and 15% are T celltype
5th most frequently diagnosed canceroverall for both males and females
males > females incidence
NHL increasing over time Hodgkin lymphoma stable
Mechanisms of lymphomagenesis
Genetic alterations Infection Antigen stimulation Immunosuppression
NHL : Etiology
cause of NHL is unknown but substantialevidence suggests:
viral cause (human T-cell leukemia-lymphoma virus, Epstein-Barr virus,hepatitis C virus, HIV)
Helicobacter pylori infection mucosa-associated lymphoid tissue (MALTlymphoma)
immunosuppression, AIDS, primaryimmune disorders
Risk factors for NHL
immunosuppression orimmunodeficiency
connective tissue disease family history of lymphoma infectious agents ionizing radiation
NHL:Pathophysiology
Most (80 to 85%) NHLs arise from Bcells; the remainder arise from T cells ornatural killer cells
Classification
Rappaport classification Lukes-Collins classification International Working Formulation
based almost entirely on morphologic criteria Revised European American Classification
(REAL) WHO classification, 2000 (most recent)
NHL: WHO ClassificationB-cell neoplasms T- and NK-cell neoplasms
Precursor B-cell neoplasm Precursor T-cell neoplasmPrecursor B-lymphoblastic leukemia/lymphoma
(precursor B-cell acute lymphoblastic leukemia)
Precursor T-lymphoblastic lymphoma/leukemia
(precursor T- cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms Mature (peripheral) T-cell neoplasmsB-cell chronic lymphocytic leukemia/small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
B-cell prolymphocytic leukemia Aggressive NK-cell leukemia
Lymphoplasmacytic lymphoma Adult T-cell lymphoma/leukemia
Splenic marginal zone B-cell lymphoma (with
or w/o villous lymphocytes)
(human T-cell lymphotropic virus type I positive)
Extranodal NK/T-cell lymphoma, nasal type
Hairy cell leukemia Enteropathy type T-cell lymphoma
Plasma cell myeloma/plasmacytoma Hepatosplenic gammadelta T-cell lymphoma
Extranodal marginal zone B-cell lymphoma of
mucosa- associated lymphoid tissue type
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sezary syndrome
Nodal marginal zone B-cell lymphoma (with or
w/o monocytoid B cells)
Anaplastic large cell lymphoma, T/null-cell,
primary cutaneous type
Follicular lymphoma Peripheral T-cell lymphoma, not otherwise
Mantle cell lymphoma
Diffuse large B-cell lymphoma
characterized
Angioimmunoblastic T-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma
Anaplastic large cell lymphoma, T/null-cell,
primary systemic type
Burkitt's lymphoma/Burkitt's cell leukemia
WORKING FORMULATION Clinically very useful and practical Divides lymphomas into : 1. Low grade 2. Intermediate grade and 3. High grade NHL
based on aggressiveness Based on morphology (Architecture
and Cell size)
Low grade /Indolent NHL Are INCURABLE
Intermediate /High Grade Are more “Aggressive” but potentially
CURABLE!
NHL: Diagnosis
immunophenotyping (flow cytometry) andcytogenetics
Bone Marrow Biopsy CT scan of chest, abdomen and pelvis Lumbar Puncture if CNS symptoms or aggressive
lymphoma with bone marrowinvolvement
peripheral blood
Diagnosis of NHL
Biopsy of lymph node is preferred toshow nodal architecture (follicular regionvs. diffuse).
Flow cytometry: CD 19, CD20 for B cell lymphomas CD 3, CD 4, CD8 for T cell lymphomas
NHL:Clinical manifestations
Variable severity: asymptomatic to extremely ill time course: evolution over weeks, months, or
years
Systemic manifestations fever, night sweats, weight loss, anorexia,
pruritis
Local manifestations lymphadenopathy, splenomegaly most common
any tissue potentially can beinfiltrated
NHL: Staging Ann Arbor StagingSystem I :indicates that the cancer is located in a single
region, usually one lymph node and thesurrounding area
II :indicates that the cancer is located in twoseparate regions, an affected lymph node ororgan and a second affected area, and that bothaffected areas are confined to one side of thediaphragm - that is, both are above thediaphragm, or both are below the diaphragm.
III: Involvement above and below diaphragm IV: Diffuse or disseminated involvement of 1 or
more extralymphatic tissues or organs (A= Absence of systemic symptoms, B= Presence
of B symptoms)
Staging of lymphoma
Stage I Stage II Stage III Stage IV
NHL: Ann Arbor Staging System
Suffix ‘A’ means absence of B symptoms Suffix ‘B’ means presence of B symptoms Suffix ‘E’ means extra nodal (not in
the lymph nodes) disease Suffix ‘S’ means splenic involvement Suffix ‘X’ means bulky disease argest
deposit is >10 cm large For example: Stage IIIB-S means disease
above and below the diaphragm, with Bsymptoms and Splenic involvement
NHL: Two most commonsubtypes
Diffuse Large Cell Lymphoma 39%
Follicular Lymphoma21%
Follicular lymphoma
most common type of “indolent” lymphoma lymphoma of follicle center B-cells (centrocytes and
centroblasts), usually widespread at presentation often asymptomatic not curable cell of origin: germinal center B-cell Prefer treatment if asymptomatic (“watch-and-wait”) several chemotherapy options if symptomatic median survival: years although considered “indolent”, morbidity and mortality
can be considerable transformation to aggressive lymphoma can occur
NHL :Diffuse large cell Lymphoma Commonest subtype most common type of “aggressive”
lymphoma usually symptomatic extranodal involvement is common cell of origin: germinal center B-cell treatment should be offered curable in ~ 40%
Treatment: Diffuse large cellLymphoma Limited stage (I or II) Non bulky: Combination of abbreviated chemotherapy (3-
4 cycles of CHOP) and radiation
Advanced Stage (III or IV) or bulky disease: Full 6-8 cycles of chemoRx with additional
XRT to bulky areas
Rituximab
Chemotherapy regimen is CHOP:Cyclophosphamide, Hydroxydoxorubicin,Oncovin and Prednisone)
Other ImportantNon Hodgkins Lymphomas Mantle Cell Lymphoma: due to CD5 positive
antigen-naive pregerminal center B-cell within the mantlezone that surrounds normal germinal center follicles
comprising about 6% of NHL cases subtype of B-cell lymphoma essentially is an
abnormal break and subsequent translocation ina gene that causes the cells to divide too earlybefore becoming capable of helping to fightdiseases
do not die as they should therefore accumulate in the lymphoid system
Burkitt’s Lymphoma African variety: jaw tumor, strongly linked
to Epstein-Barr Virus infection. Most rapidly growing human tumor. associated with a chromosomal
translocation of thec-myc gene. Thisgene is found at 8q24.
Classification:Burkitt’s Lymphoma
endemic variant occurs in equatorialAfrica. It is the most common malignancyof children in this area
involves the jaw or other facial bone,distal ileum, cecum, ovaries, kidney orthe breast.
Sporadic type of Burkitt lymphoma -(alsoknown as "non-African") is another formof non-Hodgkin lymphoma found outsideof Africa.
jaw is less commonly involved
Immunodeficiency-associated Burkittlymphoma is usually associatedwith HIV infection or occurs in the settingof post-transplant patients who are takingimmunosuppressive drugs. Burkittlymphoma can be one of the diseasesassociated with the initial manifestationof AIDS.
Microscopic exam
tumor consists of population of mediumsize lymphoid cells with high proliferativeactivity and apoptotic activity. The "starrysky" appearance
Gastric MALT Lymphoma: formof lymphoma involving the mucosa-associated lymphoid tissue (MALT),frequently of the stomach, but virtuallyany mucosal site can be afflicte
associated with chronic inflammation as aresult of the presence of Helicobacter pylori
treatment with antibiotic eradication of H.pylori
Small Lymphocytic lymphoma andChronic Lymphocytic Leukemia: is atype of non-Hodgkin lymphomacharacterized by an excess of whiteblood cells in the lymph nodes.When cancer cells are found in the bloodand bone marrow the disease is calledchronic lymphocytic leukemia (CLL).
is very indolent but relentless, withmedian survivals of almost a decade.
predominantly in older individuals.
Mycosis Fungoides
Malignancy of helper T cells. Affinity for skin. Can be treated with electron beam
radiation, ultraviolet light, or topicalalkylating
SummaryNON HODGKINS LYMPHOMA Extremely heterogenous group of
disease WHO classification is probably going to
stay Indolent NHL : Slow growing but
incurable Aggressive NHL: Faster growing
but/therefore potentially curable Follicular NHL: Commonest indolent
type DLCL: Commonest aggressive type
THANKYOUU…
questions
Which type of lymphoma has noReed-Sternberg Cell uponmicroscopic examination?
a.Hodgkin’s lymphomab.Non- Hodgkin’s lymphoma
2.Which type of lymphoma occurs at ahigher percentage than the other?
a.Hodgkin’s lymphomab.Non- Hodgkin’s lymphoma
3. Which cell type comprises more than80 % in NHL?
a. B cellb. T cell
4. Most common type of “indolent”lymphoma
a. Diffuse large cell Lymphomab. Follicular lymphomac. Mantle Cell Lymphomad. None of the above
5. Most common type of “aggressive”lymphoma
a. Diffuse large cell Lymphomab. Follicular lymphomac. Mantle Cell Lymphomad. None of the above