L26- WBC Pathology IV Flashcards by Connor Patrick

lymphoid neoplasms include (1)

myeloid neoplasms include (2)

Non-Hodgkin Lymphoma / Leukemia (including plasma cell neoplasms)
Hodgkin Lymphoma

acute myeloid leukemia (AML)
chronic myeloproliferative neoplasms (MPN)
myelodysplastic syndrome (MDS)

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Myeloid neoplasms arise from (1) cells in the (2) primarily. (3) and (4) can sometimes also be affected secondarily. (5)- list the categories of myeloid neoplasms.

1- myeloid hematopoietic progenitors cells (erythroid, granulocytic, megakaryocytic lineages)
2- bone marrow
3- peripheral blood
4- hematopoietic organs: spleen, liver, LNs

5- AML, MPN, MDS

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AML most affects (1) age group and usually block (2) development. (3) will then accumulate in bone marrow and peripheral blood.

1- adults, inc incidence with inc age; median age = 50 y/o
2- early stage of myeloid development
3- blasts / immature myeloid cells

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describe the forms of AML (by WHO) in terms of molecular features and outcome

(formerly M0-M7)
-AML w/ recurrent chromosomal translocations

AML w/ multilineage dysplasia
AML therapy related
AML not otherwise specified

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give the name for AML type M0-M7 (former WHO classification)

(degree of maturation in granulocytic lineages)
M0- minimally differentiated leukemia
*M1- AML w/o maturation
**M2- AML w/ some maturation
M3- acute promyelocytic leukemia

(presence of additional lineages of blast cells)
*M4- acute myelomonocytic leukemia
M5- acute monocytic leukemia
M6- acute erythroleukemia
M7- acute megakaryocytic leukemia

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list the technique used to distinguish between Myeloblasts

(many AML type –> many myeloblasts)

morphology
special histochemical stains (traditional)
immunophenotyping (flow cytometry, IHC)
cytogenetics (occasionally very useful)

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AML pathogenesis:

(1) will disrupt genes encoding for (2)
mutations will produce (3) genes and (4) proteins leading to (5)
additionally (6) is also present to stimulate excess proliferation
presence of (7) will cause (8)

1- translocations
2- Transcription Factors for normal differentiation
3- chimeric genes
4- abnormal fusion proteins
5- blocks terminal differentiation
6- TK mutations
7- accumulation of proliferating neoplastic precursors
8- suppress normal hematopoietic progenitors

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AML has a (slow/rapid) onset (include time frame). (2) is the most apparent symptom. Infiltration of (3) is often popular, and infiltration forming (4) is uncommon. (5) is a dangerous complication caused by (6) mutation.

1- rapid, wks-mos
2- cytopenias: either anemia, leukopenia / neutropenia, thrombocytopenia OR pancytopenia
3- mucosa, skin, soft tissue
4- extramedullary masses
5- DIC
6- t(15;17)

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DIC can be seen in type (1) AML because of (2)

1- M3, acute promyelocytic leukemia

2- t(15;17)

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AML-M3 = (1):

(2) and (3) are present within neoplastic promyelocytes
release of (4) from (3) can cause (5) due to (6) genetically

1- acute promyelocytic leukemia
2- Auer Rods
3- course azurophilic granules
4- myeloperoxidase
5- DIC
6- t(15;17)

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AML-M5 = (1):

(2) is difficult to determine on peripheral blood smear (include features)
(3) is the most useful in diagnosis, particularly (4)

1- acute monocytic leukemia
2- monocyte differentiation: presence of folded nuclear membrane in monoblast
3- skin, mucosal deposition (b/c resident macrophages go to these places)
4- gingival hyperplasia

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AML-M1 = (1):

-(2) are present in myeloblasts on peripheral blood smear

1- acute myeloid leukemia w/o maturation

2- azurophilic granules in cytoplasm

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list the techniques for diagnosis of AML, indicate the gold standard

CBC: high or low WBC count
Peripheral Blood: circulating blast cells
***BM aspirate / biopsy: >20% blasts
Flow Cytometry (surface markers)
Cytochemical staining: M1-M3 are MPO, sudan black positive, M4-M5 are estarase positive
Cytogenetics

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(1) is the gold standard for diagnosis of AML, where (2) must be present for a positive diagnosis

1- bone marrow aspirate / biopsy

2- >20% blast cells

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AML Flow Cytometry:

CD(1) for myeloid stem cells
CD(2) marker of immature blast cells
CD(3) marker for subset of more mature lineages of AMLs

1- CD34
2- CD33
3- CD15

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AML cytogenetics:

(1) are the common translocations. The more translocations indicates a (2) prognosis.
(3) of chromosome (4) are common in (5) patients

1- (younger Pts) t(15;17), t(18;21), t(16;16)
2- better prognosis (unless involving chr.11)

3- deletion / monosomy
4- chr.5/7
5- adults with AML, MDS, or post-chemo/radiotherapy

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list the diagnostic methods for AML that help distinguish it from ALL (hint- 4)

Morphology: granules, Auer rods (AML)

Histochemical Stains:

AML: MPO, sudan black, esterase stains
ALL: PAS in some

Immunophenotyping: used to differentiate myeloid from lymphoid markers

**Cytogenetics

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AML treatment:
-most are treated with (1)

M3 / AML with (2) is treated with (3) to induce (4) and eventually relapse
(5) is a possible Tx for high risk AML or relapsed AML

1- combination chemotherapy

2- AML w/ t(15;17) [chimeric RARα-PML blocks differentiation]
3- ATRA (all trans retinoic acid) / vitA derivative
4- differentiation into neutrophil
(note- chemotherapy must also be done after ATRA Tx)

5- bone marrow transplant (AML still may recur)

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AML prognosis, is indicated by its (1):

-(2) is good prognosis, (3) has intermediate prognosis, (4) has poor prognosis

1- cytogenetics
2- t(8;21), inv16
3- t(15;17)
4- del. chr.5/7

AML Tx, (1) achieve remission, but (2)% of those will relapse within 5 years

1- >60%

2- >50%

list the myeloproliferative neoplasms

CML, chronic myeloid leukemia
PV, polycythemia vera
ET, essential thrombocytopenia
PMF, primary myelofibrosis

General features of myeloproliferative neoplasms:

(1) growth is evident as it fills up (2) and prevents (3)
because of (3), (4) will occur causing (5)

1- neoplastic clone growth reaching terminal differentiation (inc / dysregulated growth)
2- bone marrow
3- (suppresses) normal hematopoiesis
4- seeding to secondary hematopoietic organs: spleen, liver
5- organomegaly

Myeloproliferative neoplasms:

‘spent phase’ causes (1) in (2) types
‘blast crisis’ is the other complication seen in (3) type, converting it to (4)

1- BM fibrosis + cytopenias
2- PV, ET, PMF

3- CML
4- acute leukemia

Myeloproliferative neoplasms:

most simply explained by the abundance of (1) and the absence of (2) seen in other leukemias

1- one of the WBCs, RBCs, or megakaryocytes

2- blast cells (no arrest or accumulation)

Myeloproliferative neoplasms mostly involve a mutated (1) enzyme causing (constitutional/defective) activity. Although (3) is circumvented, (4) is importantly not impaired.

1- TK 2- constitutional activity 3- normal growth control (via GFs) => GF-indep. prolif. + survival of marrow precursors 4- differentiation

list the common genetic TK mutation for the following Myeloproliferative neoplasms: (1) CML (2) PV (3) ET (4) PM

1- t(9;22) / Philadelphia chr. (100%) [inc ABL activity] 2- JAK2 point mutation (95%) 3- JAK2 pt mut. (50-60%), MPL pt. mut.(5-10%) 4- JAK2 pt mut. (50-60%), MPL pt. mut.(5-10%)

CML is related to the uncontrolled production of (1) due to a defect in (2). (1) will appear like (3) cells, but without (4).

1- mature granulocytes with normal differentiation 2- pluripotent stem cell for myeloid / lymphoid lineages (morphologically only affect granulocytes) 3- neutrophils (in abundance) 4- no functionality

CML is associated with (1) genetic mutation in which (2) process results.

1- t(9;22) / Philadelphia chromosome 2- BCR gene on chr.22 is fused with ABL1 gene on chr.9 --> constitutional expression of fused protein => kinase activity and unchecked proliferation (via RAS, STAT, AKT)

CML clinical presentation: - affects (1- age, sex) populations most - presents with gradual onset of (2) sxs - (3) may be present if (4) organ is involved - (5) is used to differentiate CML from leukemoid reaction (via severe bacterial infection)

``` 1- adults (25-60 y/o), M>F 2- fatigue, weakness, loss of weight and appetite (due to suppression of normal BM) 3- abdominal discomfort 4- spleen / splenomegaly 5- peripheral blood smear ```

CML labs: - (1) appearance on PB - (2) appearance on BM - (3) cytogenetic results

1- 'left-shift' (inc young cells) leukocytosis of mostly neutrophils and precursors + inc eosinophils, basophils /// <10% blast, possible thrombocytosis 2- 100% cellular almost (hypercellularity), mainly inc granulocytic precursors + megakaryocytes (no inc in blast%) 3- t(9;22) via PB/BM

describe the course / progression of CML

(triphasic) 1) Stable phase (chronic phase): 2-5 yrs w/o effective Tx 2) Accelerated phase: after 2-5 yrs 50% of Pts progress here --> inc blast%, BM fibrosis, thrombocytopenia, extra cytogenetic abnormalities 3) Blast crisis: progression to acute leukemia w/in 1 yr; 75% myeloid, 25% lymphoid

CML Tx: list the 4 therapies

1) Imatinib: TK inhibitor (BCR-ABL kinase) /// slows disease progression, but doesn't destroy abnormal clone 2) IFN-α: slows disease progression 3) Hydroxyurea: 'gentle' chemotherapy 4) allogenic BM transplant: younger Pts, 75% cure rate

describe the classification of Polycytothemia

Reactive: due to reduced plasma volume (secondary to dehydration) Absolute: 1) primary = polycytothemia vera (PV), associated with splenomegaly and low EPO 2) secondary: appropriately (lung disease, cyanotic HD, high altitude) OR inappropriately high EPO (EPO tumors: renal, cerebellar, hepatic tumors)

PV = (1): - characterized by (2) and (3) levels in CBC - most patients present with (4)

1- polycythemia vera 2- abnormal RBC count elevation 3- abnormal elevated Hb levels 4- asymptomatic

In advanced or symptomatic PV, list the symptoms and complications that may develop

- hyperviscosity Sxs: HA, dizziness, visual disturbances - pruritus, erythromelalgia - early satiety due to splenomegaly -Polycythemia complications: thrombosis or bleeding

list the WHO criteria for PV diagnosis

Major criteria: 1) Hb >16.5 g/dL in men, >16 g/dL in women OR >48-49% Hc OR inc RBC mass 2) BM biopsy with hypercellularity, prominent proliferation of all cells 3) JAK2 mutation (98% cases) Minor criteria: -low EPO levels (subnormal serum EPO) Need all 3 majors OR 2 major + minor

Primary Myelofibrosis is a neoplasm of (1) cells. The release of (2) CKs will cause the characteristic (3) in BM.

1- megakaryocytes 2- PDGF, TGF-β 3- obliterative bone marrow fibrosis

Primary Myelofibrosis: - (1) common genetic mutations - (2) age group is most affected - patient commonly present with (3) and (4) - complications include (5)

1- JAK2 (--> activates JAK-STAT) 2- >60 y/o 3- progressive anemia (obliterative BM fibrosis) 4- hepatosplenomegaly (extramedullary hematopoiesis) 5- infections, bleeding disorder, transformation into AML

Primary Myelofibrosis Dx: - (1) on PB - (2) on BM - (3) spleen appearance

1- leukoerythroblastosis (extramedullary hematopoiesis) + immature appearing RBCs/WBCs (RBCs with tear drop appearance / poikilocytes) 2- hypocellular, diffuse fibrosis w/ entrapped megakaryocytes 3- massive (splenomegaly), subcapsular infarcts

ET = (1): - (2) are the common mutations - (3) is the characteristic feature or definition

1- essential thrombocytopenia 2- JAK2, MPL mutations 3- inc / abundance of abnormal platelets (neoplastic megakaryocytes)

ET = (1): - mostly affects (2) age group - (slow/rapid) onset - occasionally (4) is a major complication

1- essential thrombocytopenia 2- >60 y/o 3- slow, indolent growth 4- thrombosis: DVT, portal vein / hepatic vein thrombosis, erythromelalgia (hand/foot burning due to arteriolar occluasion)

ET appearance on: - (1) PB - (2) BM

1- abnormally large platelets | 2- inc megakaryocytes w/o fibrosis (vs PMF)

MDS = (1): - (2) is definition - (3) is the main cause affecting (4) age group with (slow/rapid) onset - (6) is the other cause

``` 1- myelodysplastic syndrome 2- clonal maturation defects in stem cells --> ineffective hematopoiesis / abnormal differentiation --> cytopenia 3- idiopathic/primary 4- >50 y/o 5- slow, gradual 6- 2-8 yrs post-chemo/radio-therapy ```

MDS = (1): - many cases transform into (2) - deaths are related to (3) - median survival rate is (4)

1- myelodysplastic syndrome 2- AML (10-40% cases) 3- cytopenia complications 4- 9-30 mos (only 2-4 mos in therapy related MDS)

MDA appearance on: - (1) PB - (2) BM

1- macrocytic anemia, cytopenia +/- blast cells 2- RBC morphological abnormality +/- granulocytic precursors, +/- megakaryocytes

list the diagnostic techniques for MDS

1) CBC, PB: various cytopenias (partial or full pancytopenia) 2) BM morphology: hypercellular, disorganized hematopoiesis 3) cytogenetic abnormalities: chr.5/7 deletion, trisomy 8 4) flow cytometry

MDS Tx

- allogenic bone marrow transplant (younger patients) | - supportive Tx (older patients)