Leukemias and Myeloid Disorders 1 Flashcards
Leukemia defined
Neoplastic proliferation of hematopoeitic cells
Lymphomas and leukemias
Can be caused by the same cell types
Lymphomas are solid neoplasms of lymphoid cells outside the marrow
Leukemia leading cause of cancer death
In children/young adults
Which are most common
Acute and chronic each half
AML most common acute, CLL most common chronic
Sex and luekemia
Male mostly
Especially Hairy cell leukemia and T cell ALL
Inherited genetic and chromosomal risk for leukemia
Down sydnrome
Fanconis anemia
Radiation and drugs and leukemia
Radiation - increased risk of all except CLL
Drugs - alkylating agents, topoisomerase inhibitors increase risk of acute
Smoking increase AML risk
Viral and leukemia
Human T cell leukemia virus and T cell leukemias/lymphomas
EBV or HHV-8
Immune and leukemia
Chronic immune stimulation and immunodeficiency associated with increased risk
Mutations (common)
t(9;22) - Philly - Most CML and some ALL
t(15;17) - in promyelotic AML (retinoic acid receptor fuses with PML…tx with trans-retinoic acid)
t(8;21) in AML with maturation (favorable)
in(16) in AML with myelomonocytic diff and abnormal eosinophils (favorable)
t(12;21) in favorable ALL
11q23 (MLL gene) infantile ALL t(4;11), some AML following topoisomerase inhibitors (bad prognosis)
Trisomy 8, momnosomey, of chromosomes 5 and 7 associated with AML and myelodisplastic disroders
Acute vs chonirc leukemia
Acute - fatal…at least 20% blast cells…sudden onset…marked cytopenias and more symtpoms
Chronic - greater cell maturation…better survival…more prominent splenomegaly…more gradual symptoms and mild cytopenias
Clinical manifestations
Bone marrow - neutropenia, thrombocytopenia, anemia
Organ infiltration
INcreased metab and cell lysis
Bone
Lymphadenopathy
Splenomegaly
Types of leukemias
Bone pain, espeically in acute
LAD - in lymphoctyic anemias, mostly CLL
Spleno - Mild to mod in acute, mod in CLL, most in CML
Hepato
CNS
Skin
Myeloid sarcomas and leuk
Hepato - most in CLL
CNS - espeically ALLs, some AMLs
Skin - T cell and monocytic leukemias
Mye Sarc- bone or soft tissue infiltrates in AML
Cytochemistry used for
AML for most part
Cytogenics used for
CML confirmatory…subtypes of acute
ALL types
Precursor B or T lymphoblastic leukemia
Same cell may cause lymphoma but if 25% or more lymphoblasts in marrow then leukemia
Most common patients with ALL
Children, adolescents (most common in childreN)
More in men
ALL subtype and flow cytometry…also symptoms
Bone pain, CNS< tests
May have low white count
Precurosr T (15%) - Mediastinal mass or lymphoma common )…more common in males
Prognosis, morphology of ALL
95% of childrne into remission
Round and convoluted nuclei, small to medium with little cytoplasm, high grwoth rate
AML primary population
Most adults and more male
AML classifcation
Need cytogenics Recurring cytogenic abn (8;21), t(15;17) Mylodysplasia related changes Therapy related NOS
AML onset
Gum hyperplasia (esp in monocytic) DIC in promyelocytic, may be aleukemic
Morphology and flow cytometry and prognosis of AML
Auer rods…positive nezym estains
60% remission but most relapse
Favorable and unfavorable AML
Favorable - t(8;21), promyelocytic t(15;17), inv(16), isolated NPM 1 mutation
Unfavorable - AML with myelodysplasia changes (del 5,7), therapy related AML, FLT3 mutations
Acute promyelocytic leukemia
t(15;17)
Abnormal RAR…can lead to DIC
Look for multiple auer rods and intense granularity
ATRA is the therpay
Acute leukemia of ambiguous lineage
Primitive acute leukemias showing either insufficienct evidence of lymphoid or myeloid differentiation OR showing both myeloid and lymphoid or bothB and T cell differentiation
Typically a poor prognosis
B lymphoid-myeloid cases mutations
t(9;22) or 11q23 (MLL)
CML mutation and ages
t(9;22) - Philly…c-abl transferred to bcr region of 22…increased tyrosine kinase activity…more cell division…doesn’t block differentiation
26-60
Symptoms of CML and what to look for
Splenomegaly
Netutrophilia with less than 5% blasts and all stages of myeloid precursors…basophilia
100% cellular bone marrow with increased small MK but full granulocytic maturation
Thrombocytosis in 50%
CML blast phase
After about 3 years.
Myeloid - 70%
Lymphoid - 30%
Effect of MLL mutation, BCR-ABL mutation and RAR mutation
MLL - increased self renewal
BCR-ABL - increased growth and survival
RAR - differentiation blocked
Philly chromosome mutation and what it causes
CML and ALL
BCR-ABL fusion protein from t(9;22) is tyr kinase that activates pro-growht and survival
t(15;17) mutation
AML (promyelocytci)
PML-RARE fusion creates abnormal RAR
Core binding factor mutations
Disrupt TF needed (usually good prognosis)
t(8;21) - AML with maturation
inv (16) - monocytic AML with abnormal eosino
t(12;21) - favorable ALL`
MLL mutation
11q23
Poor
Histone modifying protein that allows prolif pathways to be turned on
Mature B cell and plasma cell markers
Kappa and lambda light chains
First tier of AML diagnosis
Cytogenics
In a nutshell
Is it acute leukemia (more than 20% blasts)…if yes then myeloid or lymphoid (flow)…if lymphoid, B or T (flow)…if myeloid, does it have recurring CG abnormality)..if not, then is there associated dysplasia or histroy of chemo or XRT…if not, is there maturation
Things for good diagnosis of precurosr B cell ALL
Hyperdiploidy
t(12;21) mutation
Age 2-10 with lower WBCs at diagnosis
Poor prognosis of B cell ALL
Hypodiploidy Under 1 or over 10 Higher WBC t(9;22) - BCR/ABL, Philly t(4;11) - AF4/MLL
AML with maturation
t(8;21) good prognosis
Core binding factor mutations
Myelomonocytic AML
Inv (16) or t(16,16)
Abnormal eosinophils
Monocytic AML
11q23 MLL abn
Poor prognosis
Promyelocytic AML
t)15;17)
Distinctive granules with Auer rods and DIC
Good prognosis if treated
NPM1, FLT-3 and CEBPA
In AML with normal CG, prognositc significance
FLT-3 duplication - bad NPM 1 - good CEBPA - good FLT3 plus NPM1 - IM FLT3 plus CEPBA - ?
Alkylating agent and toposiomerase related changes
Alkylating - chr 5,7 loss
Topo - 11q23
