Hematologic Malignancies & Myeloproliferative Disorders Flashcards
General definition of acute leukemia
A hematopoietic neoplasm characterized by over-proliferation of immature blast cells that “crowd out” the normal blood-producing cells in the marrow; characterized by falling peripheral blood counts
May be of lymphocytic or myeloid origin, identified by immunohistochemistry
Presentation is related to thrombocytopenia (bleeding, bruises), neutropenia (infection), and erythrocytopenia (fatigue, dyspnea)
General definition of chronic leukemia
Hematopoietic neoplasm characterized by increased WBC count due to the accumulation of normal, mature blood cells, often with insidious onset
May be of lymphocytic or myeloid origin
3 viruses with oncogenic roles in lymphoma
- Epstein Barr Virus (EBV) - Hodgkin lymphoma, Burkitt lymphoma, other B cell non-Hodgkin lymphoma
- Human T Cell Leukemia Virus 1 (HTLV-1) - adult T cell leukemia / lymphoma (ATLL)
- Kaposi Sarcoma Herpesvirus / Human Herpesvirus-8 (KSV/HHV-8) - primary effusion lymphoma
Epidemiology of hematologic malignancies in children
Leukemia is the most common childhood cancer (37%)
Lymphoma is the 3rd most common childhood cancer (24%)
Myelodysplastic Syndrome (MDS)
A group of conditions in which the marrow is overtaken by a neoplastic clone that is incapable of making normal, effective blood cells in one or more myeloid lineages, replacing normal marrow
These dysplastic clones are not characterized by the same genetic hits that lead to blocks of maturation in leukemias, although patients are at higher risk of acquiring these hits leading to transformation to AML
Myeloproliferative Neoplasms (MPNs)
A group of conditions in which the marrow is overtaken by a neoplastic clone that over produces functioning blood cells, usually in multiple lineages, with corresponding increase in marrow cellularity
Usually insidious onset with splenomegaly and/or hepatomegaly due to sequestration of excess blood cells and extramedullary hematopoiesis
May transform to AML, MDS, or bone marrow failure
Classical Hodgkin Lymphoma (CHL)
Lymphoma derived from B cells (more on this later)
Non-Hodgkin Lymphoma
Refers to any malignancy derived from mature lymphocytes, excluding CHL; subdivided into B cell NHLs (more common) and T cell / NK cell NHLs (less common)
Acute Lymphoblastic Leukemia (ALL)
Clonal, neoplastic proliferation of immature lymphocytes (B or T cell lineage), usually blasts - clonal progeny of the affected lymphoid stem cell commit to a B or T cell lineage but maturation is blocked before mature T and B lymphocytes are formed
75% of cases of ALL occur in children under 6 years old
Risk factors: previous chemotherapy, especially DNA alkylating agents and topoisomerase inhibitors, ionizing radiation, benzene exposure, tobacco smoke
Presentation: Anemia and pallor, thrombocytopenia, hemorrhage, ecchymoses, petechiae, fever and infection, adenopathy, hepatosplenomegaly
CD34
Generic marker of leukocyte immaturity; expressed by lymphoblasts AND myeloblasts (not specific)
TdT
Lymphoblast cell surface marker (not found on mature lymphocytes); not specific for B-cell or T-cell lineage
Cell surface markers of B cell lineage
CD19, CD20, CD22
Cell surface markers of T cell lineage
CD3, CD4, CD5, CD8
B-ALL - Demographics, cytogenetics, and subtypes
Majority (80-85%) cases of ALL and the typical ALL of childhood
B-lymphoblasts express B-lineage antigens (CD19, CD22) but do not express markers of mature B cells (CD20, sIg)
t(9;22) - BCR-ABL (Ph+)
MLL translocation
t(12;21) ETV6-RUNX1
T-ALL
Minority of ALL cases (25-30%), more frequently seen in adolescents and young adults, favoring males; more likely to present with a T-lymphoblastic lymphoma component, often manifesting as a large, mediastinal mass
T-lymphoblasts express T-lineage antigens CD2, CD3, and CD7
May express CD4 and/or CD8
Often express CD99 and CD1a (immature T cell markers)
t(9;22) - BCR/ABL (Philadelphia Chromosome) in B-ALL
Common cytogenic abnormality of B-ALL
Encodes a fusion tyrosine kinase protein; the fusion protein seen in ALL differs from the protein seen in CML by size (p190)
BCR-ABL (Ph+) ALL has the worst prognosis of any subtype of ALL
Prognostic factors for ALL
Age: Better in school age children (2-10), worse in infants, teens, adults
WBC count: Worse if markedly elevated
Hyperdiploidy: Better with 51+ chromosomes, worse with <46 chromosomes
T-ALL has a worse prognosis than B-ALL
MLL gene Abnormalities (in B-ALL)
Common cytogenic abnormality of B-ALL
Frequently seen in neonates and infants
Poor prognosis
Auer Rods
Visualized as pink lines in the cytoplasm of myeloblasts on peripheral smear; allows positive identification of a blast as a myeloblast
t(12;21) ETV6-RUNX1
Common cytogenic abnormality of B-ALL
Accounts for 25% of all childhood B-ALL cases
Favorable prognosis
Signs and symptoms of acute leukemia
Signs related to replacement of normal blood lineages with immature blasts:
Anemia and pallor, thrombocytopenia, hemorrhage, ecchymoses, petechiae, fever and infection, adenopathy, hepatosplenomegaly
Signs directly attributable to proliferation of leukemic cells: thrombotic events due to increased blood viscosity (leukostasis), DIC, infiltration of skin, gums, and lymph nodes by leukemic cells
On marrow biopsy, blasts represent a majority of marrow cells; determination of blast type requires immunophenotyping
Symptoms; Fatigue, malaise, dyspnea, bruising, weight loss
Immunophenotype & Diagnosis of AML
CD34 - genetic marker of immaturity; not lymphocyte / myelocyte specific
CD117 (c-Kit), Myeloperoxidase - genetic markers of myeloid lineage (not seen on lymphoblasts)
Myeloblasts present in the marrow and/or peripheral blood at > 20%; myeloblasts are identified by the presence of Auer Rods
Immunophenotype & Diagnosis of ALL
CD34 - genetic marker of immaturity; not lymphocyte / myelocyte specific
TdT - genetic lymphoblast marker (not found on mature lymphocytes); not B/T specific
CD19, CD22 - B cell lineage markers
CD3, CD7 - T cell lineage markers
t(8;21) RUNX1-RUNX1T1
Presence of this translocation is diagnostic for AML regardless of blast count
RUNX1 codes for the alpha unit of core binding factor (CBF), a TF needed for hematopoiesis; the fusion protein blocks transcription of CBC-dependent genes, blocking differentiation
Accounts for 5% of AML cases, seen in younger patients (30s/40s) with good prognosis
inv(16) or t(16;16) CBFB-MYH11
Cytogenic abnormality of AML; 5-10% of cases; CBFB encodes the beta subunit of core binding factor (CBF)
Marrow may show immature eosinophils with abnormal basophilic granules - “Baso esos”
Usually presents as myelomonocytic leukemia, a mixture of increased myeloblasts and monocytes
Usually seen in younger patients (30s/40s) with good prognosis
t(15;17) PML-RARA
Acute promyelocytic leukemia (APL); presence of this translocation is diagnostic for PML regardless of promyelocyte count; 5-10% of cases
The RARA gene encodes the retinoic acid receptor alpha protein; signaling through this receptor is required for promyelocyte differentiation
Prognosis is good with treatment: supra-physiologic doses of all trans retinoic acid (ATRA) in place of primary induction chemotherapy
Risk of DIC
t(1;22) RBM15-MKL1
Common cytogenic abnormality of AML
Most often seen in infants with Down Syndrome, with good prognosis
Characterized by abnormalities in megakaryoblast differentiation
AML with abnormalities of 11q23 MLL
MLL gene may be rearranged with multiple possible partner genes
Poor prognosis
Also seen in ALL
t-AML
AML arising secondary to DNA damage from prior therapy, especially alkylating agents and radiation or topoisomerase inhibitors
tAML secondary to alkylating agents or radiation exhibits latency 2-8 years from primary treatment; karyotype often includes whole or partial loss of chromosomes 5 and/or 7
tAML secondary to topoisomerase inhibitors exhibits latency 1-2 years from prior treatment; rearrangement of the 11q23 MLL gene is common, with very poor prognosis
Molecular prognostic markers of AML-NOS
AML-NOS lacks recurrent cytogenetic findings and is not known to be due to previous therapy
Classified on the basis of molecular abnormalities:
FLT3 ITD (internal tandem duplications in the FLT3 gene) - negative prognostic factor
Mutation in NPM1 gene - positive prognostic factor
Mutation in CEBPA gene - positive prognostic factor
2 clinical scenarios of MDs
MDS may occur as a primary disease, usually in people > 50 years old with insidious onset, or as a secondary / therapy-related disease (part of the spectrum of t-AML)
Diagnosis of MDS
Persistent cytopenia in one or more lineage
Morphologic evidence of dysplasia in at least 10% of cells in one or more lineage
Increased myeloblasts (but less than 20% of marrow and/or peripheral blood cells)
Presence of clonal cytogenic abnormality, usually whole or partial deletions of chromosomes 5 and/or 7, or trisomy 8
Morphologic findings of MDS
Dyserythropoiesis - prominent ring sisderoblasts (accumulation of iron in the cytoplasm of RBCs due to inability to incorporate iron into heme)
Dysgranulopoiesis - hypogranular cytoplasm, neutrophils with bi-lobed nuclei (Pelgeroid, pseudo-Pelger-Huet)
Dysmegakaryopoiesis - small, hypo or non-lobated nuclei
Non-neoplastic causes of secondary myelodysplasia (4)
May mimic MDS; must be ruled out if the only basis for MDS diagnosis is cytopenia and abnormal morphology
Chemotherapeutic drugs
B12, folic acid deficiency
Viral infection
Toxin exposure, especially heavy metals
Low Grade MDS - 3 subtypes
Low grade MDS is diagnosed when myeloblasts account for less than 5% of marrow cells and less than 2% of peripheral blood cells
Refratory cytopenia with unilineage dysplasia (RC-UD) - good prognosis
Refractory cytopenia with multilineage dysplasia (RC-MD) - worse prognosis, higher risk of transformation to AML
MDS with isolated deletion 5q
High Grade MDS - 2 subtypes
High grade MDS is diagnosed when myeloblasts account for 5-19% of marrow cells and 2% or more of peripheral blood cells
Refractory anemia with excess blasts-1 (RAEB-1) - 5-9% blasts in marrow or 2-5% blasts in peripheral blood; 25% chance of transformation to AML
Refractory anemia with excess blasts-2 (RAEB-2) - 10-19% blasts in marrow or 5-19% blasts in peripheral blood; 33% chance of transformation to AML
Chronic Myelogenous Leukemia (CML)
Most common MPN, manifesting primarily as persistent neutrophilia
Associated with t(9;22) BCR-ABL1 gene fusion (Philadelphia chromosome)
Chronc phase - presents as leukocytosis due to neutrophilia; bone marrow shows hypercellularity but blasts are not increased in blood
Blast phase - transformation to AML with 20% or more blasts in the marrow or blood
Treatment: Protein tyrosine kinase inhibitor Gleevec (Imatinib) or second generation Dasatinib
Polycythemia Vera (PV)
MPN characterized by erythrocytosis, usually accompanied by increased neutrophils and platelets and corresponding trilineage hyperplasia in the marrow
Associated with mutation of JAK2 gene encoding the JAK2 cell signaling protein leading to constitutive activation
Polycythemic stage is characterized by increased peripheral blood cell counts, followed by a spent phase (post-PV myelofibrosis) characterized by falling blood counts ]
Risk of thrombosis (esp. mesenteric, portal, and splenic veins)
Treatment: therapeutic phlebotomy, aspirin
Primary Myelofibrosis (PMF)
MPN characterized by proliferation of granulocytic & megakaryocytic lineages
Caused by JAK2 mutations (50% of cases)
Initially marrow is hypercellular followed by progression to fibrotic stage
Fibrotic stage is characterized by leukoerythroblastosis of the blood (often with presence of dacrocytes) and splenomegaly due to extramedullary hematopoiesis
Essential Thrombocythemia
MPN characterized by thrombocytosis
JAK2 mutations (50% of cases)
50% cases asymptomatic; may present as TIA, digital ischemia with paresthesias, thrombosis of major arteries or veins
