Hematologic Malignancies & Myeloproliferative Disorders

Question 1

General definition of acute leukemia

Answer 1

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)

Question 2

General definition of chronic leukemia

Answer 2

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

Question 3

3 viruses with oncogenic roles in lymphoma

Answer 3

1. Epstein Barr Virus (EBV) - Hodgkin lymphoma, Burkitt lymphoma, other B cell non-Hodgkin lymphoma
2. Human T Cell Leukemia Virus 1 (HTLV-1) - adult T cell leukemia / lymphoma (ATLL)
3. Kaposi Sarcoma Herpesvirus / Human Herpesvirus-8 (KSV/HHV-8) - primary effusion lymphoma

Question 4

Epidemiology of hematologic malignancies in children

Answer 4

Leukemia is the most common childhood cancer (37%)

Lymphoma is the 3rd most common childhood cancer (24%)

Question 5

Myelodysplastic Syndrome (MDS)

Answer 5

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

Question 6

Myeloproliferative Neoplasms (MPNs)

Answer 6

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

Question 7

Classical Hodgkin Lymphoma (CHL)

Answer 7

Lymphoma derived from B cells (more on this later)

Question 8

Non-Hodgkin Lymphoma

Answer 8

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)

Question 9

Acute Lymphoblastic Leukemia (ALL)

Answer 9

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

Question 10

CD34

Answer 10

Generic marker of leukocyte immaturity; expressed by lymphoblasts AND myeloblasts (not specific)

Question 11

TdT

Answer 11

Lymphoblast cell surface marker (not found on mature lymphocytes); not specific for B-cell or T-cell lineage

Question 12

Cell surface markers of B cell lineage

Answer 12

CD19, CD20, CD22

Question 13

Cell surface markers of T cell lineage

Answer 13

CD3, CD4, CD5, CD8

Question 14

B-ALL - Demographics, cytogenetics, and subtypes

Answer 14

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

Question 15

T-ALL

Answer 15

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)

Question 16

t(9;22) - BCR/ABL (Philadelphia Chromosome) in B-ALL

Answer 16

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

Question 17

Prognostic factors for ALL

Answer 17

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

Question 18

MLL gene Abnormalities (in B-ALL)

Answer 18

Common cytogenic abnormality of B-ALL

Frequently seen in neonates and infants

Poor prognosis

Question 19

Auer Rods

Answer 19

Visualized as pink lines in the cytoplasm of myeloblasts on peripheral smear; allows positive identification of a blast as a myeloblast

Question 20

t(12;21) ETV6-RUNX1

Answer 20

Common cytogenic abnormality of B-ALL

Accounts for 25% of all childhood B-ALL cases

Favorable prognosis

Question 21

Signs and symptoms of acute leukemia

Answer 21

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

Question 22

Immunophenotype & Diagnosis of AML

Answer 22

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

Question 23

Immunophenotype & Diagnosis of ALL

Answer 23

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

Question 24

t(8;21) RUNX1-RUNX1T1

Answer 24

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

Question 25

inv(16) or t(16;16) CBFB-MYH11

Answer 25

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

Question 26

t(15;17) PML-RARA

Answer 26

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

Question 27

t(1;22) RBM15-MKL1

Answer 27

Common cytogenic abnormality of AML

Most often seen in infants with Down Syndrome, with good prognosis

Characterized by abnormalities in megakaryoblast differentiation

Question 28

AML with abnormalities of 11q23 MLL

Answer 28

MLL gene may be rearranged with multiple possible partner genes

Poor prognosis

Also seen in ALL

Question 29

t-AML

Answer 29

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

Question 30

Molecular prognostic markers of AML-NOS

Answer 30

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

Question 31

2 clinical scenarios of MDs

Answer 31

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)

Question 32

Diagnosis of MDS

Answer 32

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

Question 33

Morphologic findings of MDS

Answer 33

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

Question 34

Non-neoplastic causes of secondary myelodysplasia (4)

Answer 34

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

Question 35

Low Grade MDS - 3 subtypes

Answer 35

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

Question 36

High Grade MDS - 2 subtypes

Answer 36

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

Question 37

Chronic Myelogenous Leukemia (CML)

Answer 37

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

Question 38

Polycythemia Vera (PV)

Answer 38

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

Question 39

Primary Myelofibrosis (PMF)

Answer 39

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

Question 40

Essential Thrombocythemia

Answer 40

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