3.25 STROM Hematologic Malignancies I Flashcards Preview

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Flashcards in 3.25 STROM Hematologic Malignancies I Deck (40):
1

HCT=

(RBC/Bld Vol)x(RBC vol/RBC)=RBCxMCV

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Blast Criteria

a. Big Cell

b. Increased nuclear/cytoplasm ratio

c. Immature Chromatin

d. Big nucleolus or two

e. A bunch of cell that look a like***

--Does not have to meet all the standards to be considered a blast

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Myelophthisic/Leuko-erythroblastic

What hematologic malignancies look like

-Stuff that should be in the BM is in the peripheral blood

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Immunophenotyping

-Differnent cell types express different antigens

-use mAbs to detect

-hint most markers for T-cells will be <10

-Malignancies can change surface expression so not as helpful as ppl thought it would be

-Access via flow cytometry (remember lyse RBC so will not detect poss RBC precursors)

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B-cell and T-cell Antigens

B-cell: CD-20, IgG kappa/lambda, CD45(both)

T-cell: CD3, CD7, CD4 or CD8

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CD45, CD33, CD34

Usually start with CD45: on almost all marrow cells and can help to ID a blast population (left ball of graft)

-Most blast tend to express CD34

-Maturing granulocytes tend to express CD33

-COMBO of CD33 & CD34 indicate AML if in large population (premature myeloid cell in peripheral)

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Immunohistochemistry

-Works better for larger cells than flow cytometry

-use enzyme conjugated abs to desired cell surface protein and then use CHROMOGENIC substrate

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Gilman's Hypothesis

Need to mutations for the AML to hurt the patients

Class I: increases proliferation

Class 2: decreases differentiation -together these will make the leukemia much more aggressive and dangerous

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Summary of Malignancies Arising in the BM

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AML

Rapidly proliferating clones: Blasts in marrow and often in blood stream

Can arise from 3 cell lineages:

(1) Megs

(2) Erythroid Lineage

(3) Myeloid lineage

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Acute Lymphocytic Leukemias (ALL)

Arise from the lymphocyte lineage

-Rapidly proliferating clones: blasts in marrow and often blood stream

 

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Typical Presentation of Acute Leukemias

-Clones can take over a variety of locations, usually blood stream and BM

-They can take over BM w/o raising the WBC count in peripheral

-Can sometimes present as cytopenias (decreased cellularity of the blood), would not expect a rapidly proliferating population to present as cytopenia

Blasts outside of Marrow (rare): Myeloid: Myeloid Sarcoma and Lymphoid: Lymphoblastic lymphoma

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Acute Leukemia Diagnosis

-Use to simply be >20% blast in marrow, not very predictive of how the leukemia will progress

Other methods:Morphology (useless by itself), Immunophenotyping (blasts can change surface expression) and genotyping

-Use an many as possible, genotyping can predict AML even if blast count is low

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Genotyping Acute Leukemias, Specific Mutations

t(15:17) PML-RARA (AML Subtype)

t(8;21) RUNX1-RUNXT1 (AML Subtype)

t(12;21) FLT3 mutation(+) (AML Subtype)

-These and others give increased prognostic value, predicts response to therapy, IDs molecular targets for therapy development

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Gililand Hyposthesis AGAIN!!

Class I (proliferation/survival advantage):

-FLT3-ITD, FLT3-TKD, Kit, Ras, PTPN11 Jak2 (usually dectected via sequencing)

Class II (impaired differentiation/apoptosis):

-t(15;17) PML-RARA, t(8;21) Runx-Runx1T1, (inv(16) or t(16;16)))CBFB-Myh11, MLL fusions (usually detected via cytogenetics)

BOLDED= AML diagnosed with presence even w/o blast count

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AML with AUER RODs

t(8;21) Runx-1-Run1T1 Mutation

Clinical Presentation: younger patients/kids

Auer rods: crystalization of granule contents (excess myeloperoxidase production)

Immunophenotype: CD34+, CD13+, CD33weak

Prognosis: good response to chemo

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APL: PML-RARA

t(15;17) fusion of PML (trans factor) with RARA (retinoic acid receptor)

-Class II mutation: Inhibits granulocyte differentiation

-TREATMENT: All Trans Retinoic Acid (ATRA), induces cell differentiation of the blasts to granulocytes (CLINICAL REMISSION)

-CLINICAL PRESENTATION: DIC, SEVERE THROMBOCYTOPENIA***

-Morphology: AUER RODS in stacks (faggot cells)*** sometimes see Bi-nuclear appearance

Immunophenotype: Weak/absent: CD34, HLA-DR, CD13+, CD33+

Prognosis: good if diagnosis is made

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AML: CBFB-MYH11

inv(16) or t(16;16)

-Class II mutant, clinical presentation: younger patients/kids

-Morphology: Myelomonocytic* (mixed granulocyte-monocyte feats), Increased Eosinophils in blood and marrow (not known why)

-Immunophenotype: CD34+, CD117+ (blasts); CD13+, CD33+ (granulocytes); CD14+, CD11b+ (monocytes)

Prognosis: GOOD; optimal with high dose CYTARABINE

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AML w/ Normal Cytogenetics 

40-50% of AML cases

-Any age group

Morphology: undifferentiated or variable granulocytic or monocytic/monoblastic

-Immunophenotype: blast markers (CD34, CD117)+, can show any lineage markers

-Prognosis: have to look at molecular genetics, pairing of mutation will determine 

-For some BM transplant doesnt help (NPMN! or CEBPA+, FLT3-ITD-, 60% 4-yr survival)

-for other it will (FLT3-ITD+ or NPM1-, CEBPA-, FLT3-ITD-, ~29% 4-yr survival)

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ALL (Acute Lymphoblastic Leukemias)

TdT: important for VDJ recombination and marker of B and T cells

-CD19,CD10 and uCD20 are markers of B cells, can also express myeloid markers (CD13, CD33)

-Can also express CD34 (GENERAL BLAST MARKER*****)

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ALL: BCR-ABL1

-t(9;22), proliferation activator (class I), diff from the mutation found in CML which is a class II mutation and prevents maturation of the cell, and have similar cytogenetics

-Clinical Presentation: Older adults (25% of all cases)

Morphology: Big agranular blasts, hard to tell ir myeloid or lymphoid

Immunophenotype CD10+, CD19+, TdT+

Prognosis: Poor

 

 

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ALL: MLL rearranged

t(v;11q23), or t(11;19) Class II mutation, also found in AML

Clinical Presentation: most common leukemia in kids

Morphology: big agranular blasts

Immunophenotype: CD10-, CD19+, TdT+

Prognosis: Poor

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ALL, Mutations that made St. Jude Famous

-t(12;21); TEL-AML1 (ETV6-RUNX1), class II (inhibits differentition)

-Clinical Presentation: Kids, 25% of pediatric B-ALL

Morphology: big agranular blasts

Immunophenotype: TdT+, CD34+, CD20-

Prognosis: 90% cure rate

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ALL: T-ALL

-Common motif for lymphoid malignancies: oncogene>>>>Ig or TCR promoter

-Clinical Presentation: Kids 25% of pediatric T-ALL, often wih thymic mass**

Morphology: Big agranular blasts

Immunophenotype: TdT+, CD3+, CD5+, can express myeloid or B-cell antigens as well

Prognosis: High Risk: more intense chemotherapy regime, pretty good survival rate

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Myeloproliferative Disease

Definition: Chronically proliferating clones which differentiate to circulating blood cells

Chronic Myelogenous Leukemia (CML): shows blast profile

CMML (myelodysplastic/myelomonocytic): hybrid b/t myelocytes and granulocytes

-Can also see Chronic: eosinophilic, neutrophilic or mastocytosis leukemia. Need to differentiate from a Reactive condition

--Best indicator if prominence of mature to immature cells is out of order, "Myeloid Bulge" (more blasts than more mature cells)

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Myeloproliferative Diseases of Erythroid and Megs Lineages

Polycythemia Vera, elevated RBC count (erythroid lineage)

-Essential thromboythaemia/Primary myelofibrosis: elevated platelet count (meg lineage)

-Can progress to AML

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CML that is Undectable

Cryptic Translocation, Cannot see with Routine Cytogenetics

-Will progress to AML (can be myeloid or lymphoid)

PHASES: chronic, accelerated, acute

-Can also confuse with sepsis, get a BM

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Mastocytosis

--Usually presents as benign cutaneous lesions in kids (itchy) that goes away by itself

-Release of histamine can cause systemic symptoms that confuse clinician

Morphology: Aggregates of blank looking cells, round or spindle shapes, s/t with eosinophils

Immunophenotype: Tryptase+, CD117+, CD25+

Treatment: Imatinib

Prognosis: highly variable

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Polycythemia Vera

-Jak2 mutation in >95% of cases-detectable in PB leukocytes

-Clinical presentation: Thromboisis?hypertension/stroke or MI. increased RBC # 

Morphology: hypercellular marrow, erythroid hyperplasia, increased Megs

-Immunophenotype: no known features

Prognosis: >10yr survival is common, can progress to myelofibrosis MDS, acute leukemia

Epo will usually be low, one way to differ between neoplastic and reactive

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Essential Thrombocythemia

Jak2 mutation in ~50% of cases-detectable in PB

-Clinical Presentation: Thrombosis, increased platelets, can also be due to Fe deficiancy, infecion or chronic inflammation, can also have bleeding and splenomegaly

Morphology: Increased Megs (very abnormal and tend to cluster)

Immunopheno: not known, can not put Meg through flow cytometry (too fragile)

-Prognosis: >10yr survival is common, can progress to myelofibrosis MDS, acute leukema

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Primary Myelofibrosis

Jak2 mutation ~50%, disputed diagnostic criteria

-Morphology: increased Megs, bizarre shapes, clusting and fibrosis (TEAR DROPS?)

No known immunopheno

Prognosis: usually shorter survival than ET, can progress to marrow failure, acute leukemia

-Cells of bone marrow will relocate to spleen and liver: Extra-medullary hematopoiesis

Treatment: supportive care, blood transfusions, splenectomy are dangerous (pts too old, will bleed) and HSCT is curative but high mortality rate b/c pts are old as hell

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Myelodyisplasias

-Usually present as unexplained cytopenia, bicytopenia or pancytopenia

-see poorly functioning clones, mostly in elderly (>70)

5 major adult forms (best to worst prognosis): (1) Refractory cytopenia with unilineage dysplasia (2) refractory anemia with ring sideroblasts (3) myelodysplastic syndrome with isolated del(5q) (4) refractory cytopenia with multilineage dysplasia (5) refractory anemia with excess blasts

-Accumulation of several mutations over time in different mutations

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Refractory Cytopenia with Unilineage Dysplasia

Clinical pres: unexplanined cytopenai

Morphology: weird looking precursors: binucleation or irregular nuclei, can show fibrosism high or low cellularity, megaloblastoid features

Prognosis: surival unclear, rarely progresses to AML

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Refractory Anemia with Ring Sideroblasts

-Nonspecific cytogenetic abnormalities (trisomes, monosomes) may be present

-Morphology: ring sideroblasts usually with dyspoietic feats (in red cell series only)

--Iron granules form ring around nucleus 

-Prognosis: rarely progresses to AML

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MDS with Isolated del(5q)

-All the Megakaryocytes are MONOCUCLEAR

-Clinical pres: Anemia often severe, usually elderly

-Morph: megs are mononuclear

-Prognosis: good median survival; treatable with LENALIDOMIDE, 10% progress to AML

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Refractory Cytopenia with multilineage dysplasia

-Two or more lineages show dysplastic changes

-Clinical pres: Anemia often severe: usually elderly

-Morph: Granulocytes dont granulate normally (if affected), nuclei dont lobulate normally

Prognosis: Median survival 30 months, 10% progress to AML in 2 years

 

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Myelodysplastic Case Study

77y.o. man with newly diagnosed pulmonary adenocarcinoma

-anemia was not worked up completely, has had for past 2 years (b/f diagnosis): Fe studies, folate, B12 levels are all normal

-Gave chemo for initial diagnosis

-Really had Refractory Anemia with trilineage dysplasia

BM biopsy: Myeloid hyperplasia

Poor prognosis, gave chemo that made him sick and was not going to help

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ALL: T-ALL

-Common motif for lymphoid malignancies: oncogene>>>>Ig or TCR promoter

-Clinical Presentation: Kids 25% of pediatric T-ALL, often wih thymic mass**

Morphology: Big agranular blasts

Immunophenotype: TdT+, CD3+, CD5+, can express myeloid or B-cell antigens as well

Prognosis: High Risk: more intense chemotherapy regime, pretty good survival rate

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