Pathology of white cell disorders III - Zaloga

Question 1

acute myeloid leukemia (AML)

Answer 1

• divided into 4 categories by WHO classification
• (>20%) myeloid blasts for diagnosis; bone marrow biopsy
• positive for MPO+* –> Auer rods as crystal aggregates
• acute monocyte leukemia –> lacks Auer rods (MPO)
• acute megakaryocytic leukemia –> have marrow fibrosis, lack MPO (Auer rods)
• mutations –> accumulate myeloid blasts in bone marrow –> overcrowding other cells –> pancytopenia (anemia, neutropenia, thrombocytopenia)
• t(8;21) disrupts RUNX1 gene; inv(16) disrupts CBFB gene** –> blocks maturation of myeloid cells –> good prognosis with chemo
• need RUNX1/CBFB TF for proper hematopoiesis**
• sometimes get aleukemic leukemia (no blasts) –> need bone marrow exam to exclude acute leukemia
• can progress to acute leukemia if worsens (only acute leukemia contains MPO and Auer rods)**

Question 2

acute promyelocytic leukemia (APL) - subtype of AML

Answer 2

• t(15;17) –> retinoic acid receptor (RAR) fused with tumor protein PML**
• also activating mutations in FLT3** (receptor tyrosine kinase - growth factor)
• combine PML/RAR and FLT3 –> induce AML
• therapy: all trans-retinoic acid which binds receptor causing blasts to mature (best prognosis)

-pro-coagulants and fibrinolytic factors –> risk for DIC**

Question 3

markers for myeloid leukemias**

Answer 3

• monocyte or macrophage associated markers: CD11c,13,14,15,33,64**
• CD15 also seen in reed-sternburg cells

Question 4

how to confirm whether it is a myeloblast or lymphoblast?

Answer 4

• do stains or flow cytometry to detect markers
• AML is MPO+ (shows Auer rods)
• myeloblasts markers: CD34+, CD33+ (marker for immature)**
• CD15, 64 are markers for mature myeloid cells (only subset in AML express CD15, but all neg for CD64)**

Question 5

myelodysplastic syndromes (MDS)

Answer 5

• clonal stem cell disorder with maturation defects producing ineffective hematopoiesis
• high risk of progressing to AML with more mutations
• healthy cells overcrowded by dysplastic cells –> cytopenias
• due to mutations (primarily), drug toxins (secondary), or radiation (form t-MDS)
• t-MDS most rapid progression to AML***

Question 6

MDS pathogenesis

Answer 6

1. lose region on chromosome 5q encoding RPS14 –> ineffective hematopoiesis
2. gain/loss of single copies of genes aka aneuploidy (ex. increase in MYC on chromosome 8 –> trisomy 8)
3. loss of function mutation in tumor suppressor gene TP53

Question 7

MDS clinical features

Answer 7

• mean age is 70
• symptomatic due to pancytopenia
• more cytogenetic abnormalities –> progress to AML**
• t-MDS (from radiation) has worse survival than regular MDS

Question 8

MDS morphology

Answer 8

• dysplastic hematopoiesis with hypercellular growth
• affects erythroid, granulocytic, monocytic, megakaryocytic lineages
• ring sideroblasts in RBCs**
• Pseudo-Pelger-Hüet cells*** (benign, fewer lobes in granulocytes)

Question 9

myeloproliferative disorders

Answer 9

• proliferation of every mature myeloid cell
• constitutively activated tyrosine kinases** (due to growth factor binding or activating mutations of kinase inhibitors)
• originate in multipotent myeloid progenitors –> proliferation doesn’t stop maturation –> cytopenias
• can get splenomegaly and progress to AML

Question 10

chronic myeloid leukemia (CML)

Answer 10

• mutation in BCR-ABL fusion gene* due to t(9;22) on Philadelphia chromosome 22 –> constitutive ABL kinase activation –> survival/growth
• drives granulocytic/megakaryotic progenitor proliferation
• ABL on chromosome 9
• BCR on chromosome 22
• splenomegaly (extramedullary hematopoiesis - packed with immature myeloid cells) in accelerated phase –> anemia and thrombocytopenia and increased basophils**
• accelerated phase can progress into acute leukemia (AML or ALL - blast crisis)**