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DD & BL Unit 2 > Hematologic Malignancies & Myeloproliferative Disorders > Flashcards

Hematologic Malignancies & Myeloproliferative Disorders Flashcards

1
Q

General definition of acute leukemia

A

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)

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2
Q

General definition of chronic leukemia

A

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

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3
Q

3 viruses with oncogenic roles in lymphoma

A
  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
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4
Q

Epidemiology of hematologic malignancies in children

A

Leukemia is the most common childhood cancer (37%)

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

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5
Q

Myelodysplastic Syndrome (MDS)

A

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

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6
Q

Myeloproliferative Neoplasms (MPNs)

A

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

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7
Q

Classical Hodgkin Lymphoma (CHL)

A

Lymphoma derived from B cells (more on this later)

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8
Q

Non-Hodgkin Lymphoma

A

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)

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9
Q

Acute Lymphoblastic Leukemia (ALL)

A

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

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10
Q

CD34

A

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

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11
Q

TdT

A

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

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12
Q

Cell surface markers of B cell lineage

A

CD19, CD20, CD22

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13
Q

Cell surface markers of T cell lineage

A

CD3, CD4, CD5, CD8

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14
Q

B-ALL - Demographics, cytogenetics, and subtypes

A

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

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15
Q

T-ALL

A

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)

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16
Q

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

A

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

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17
Q

Prognostic factors for ALL

A

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

18
Q

MLL gene Abnormalities (in B-ALL)

A

Common cytogenic abnormality of B-ALL

Frequently seen in neonates and infants

Poor prognosis

19
Q

Auer Rods

A

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

20
Q

t(12;21) ETV6-RUNX1

A

Common cytogenic abnormality of B-ALL

Accounts for 25% of all childhood B-ALL cases

Favorable prognosis

21
Q

Signs and symptoms of acute leukemia

A

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

22
Q

Immunophenotype & Diagnosis of AML

A

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

23
Q

Immunophenotype & Diagnosis of ALL

A

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

24
Q

t(8;21) RUNX1-RUNX1T1

A

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

25
Q

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

A

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

26
Q

t(15;17) PML-RARA

A

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

27
Q

t(1;22) RBM15-MKL1

A

Common cytogenic abnormality of AML

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

Characterized by abnormalities in megakaryoblast differentiation

28
Q

AML with abnormalities of 11q23 MLL

A

MLL gene may be rearranged with multiple possible partner genes

Poor prognosis

Also seen in ALL

29
Q

t-AML

A

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

30
Q

Molecular prognostic markers of AML-NOS

A

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

31
Q

2 clinical scenarios of MDs

A

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)

32
Q

Diagnosis of MDS

A

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

33
Q

Morphologic findings of MDS

A

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

34
Q

Non-neoplastic causes of secondary myelodysplasia (4)

A

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

35
Q

Low Grade MDS - 3 subtypes

A

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

36
Q

High Grade MDS - 2 subtypes

A

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

37
Q

Chronic Myelogenous Leukemia (CML)

A

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

38
Q

Polycythemia Vera (PV)

A

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

39
Q

Primary Myelofibrosis (PMF)

A

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

40
Q

Essential Thrombocythemia

A

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

DD & BL Unit 2 (7 decks)

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