L26- WBC Pathology IV Flashcards
lymphoid neoplasms include (1)
myeloid neoplasms include (2)
1:
- Non-Hodgkin Lymphoma / Leukemia (including plasma cell neoplasms)
- Hodgkin Lymphoma
2:
- acute myeloid leukemia (AML)
- chronic myeloproliferative neoplasms (MPN)
- myelodysplastic syndrome (MDS)
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
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
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
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
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)
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
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)
DIC can be seen in type (1) AML because of (2)
1- M3, acute promyelocytic leukemia
2- t(15;17)
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)
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
AML-M1 = (1):
-(2) are present in myeloblasts on peripheral blood smear
1- acute myeloid leukemia w/o maturation
2- azurophilic granules in cytoplasm
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
(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
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
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
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
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)
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)
