Intro and Pathology of Leukemia Flashcards
Leukemia vs. lymphoma
Leukemias are malignancies that typically involve marrow and (usually) blood
Lymphomas are malignancies that typically form discrete masses in tissue, often lymph nodes (‘oma’)
This classification refers to the typical form of a given disease; you may exceptionally have something classified as a leukemia that spares the marrow and forms a mass, or a lymphoma that involves the marrow and blood extensively.
Some diseases can fit fairly well into either category
Myeloperoxidase (MPO)
Stains granules in myeloid cells
- myeloblasts are usually characterized by positive cytoplasmic staining for MPO
- crystal aggregate of MPO may be seen as Auer rods
Leukocyte common antigen
CD45 –> found on vast majority of leukocytes
B cell immunostains
Early = TdT, CD10
Early + late = CD19 + CD20
Late = CD38
Plasma cell = CD138
T cell immunostains
Early = TdT, CD1, CD2, CD5, CD7
Late = CD3, CD4, CD8
Flow cytometry
Cells are labeled while in a fluid medium, and passed through an automated detector one cell at a time
May be sorted by more than one parameter simultaneously
Immunostains often used
Other parameters also usable (e.g., cell size)
Extremely useful for classification of tumors and determination of prognostic features
Requires viable cells
Cytogenetics
- G banding
- FISH
G-banding = Chromosomes separated during metaphase
- Stained with Giemsa (hence, G-band)
- Each chromosome has its own typical pattern
FISH (Fluorescence In-Situ Hybridization) = Probes directed at specific sequences on chromosomes
Risk factors/etiologies of leukemias/lymphomas
Chromosomal anomalies
- Nonrandom mutations
- Predominantly translocations
- May be acquired during receptor gene rearrangement
- These are often specific or characteristic for a disease or group of diseases
Heritable conditions
- Genetic instability (e.g., Fanconi’s, Bloom)
- Down Syndrome
- NF1
Viruses
Inflammatory conditions –> infectious/autoimmune
Iatrogenic –> radiation/chemo
Smoking
Major disease groups
Myeloid
- Acute myeloid leukemia (AML)
- Myeloproliferative (including CML)
- Myelodysplastic syndromes
Lymphoid
- ALL
- CLL
Myeloid neoplasms
- Derived from granulocyte precursors
- Primarily involve marrow –> may involve other hematopoietic organs
- Acute myeloid leukemias
- Chronic myeloid leukemias (may progress to AML)
AML
Neoplastic accumulation of immature myeloid cells in the bone marrow
- at least 20% blasts in marrow or blood
Types of blasts
- Myeloblast = granulocyte precursors
- –> characterized by positive cytoplasmic staining for MPO
- –> crystal aggregates of MPO may be seen as Auer rods - Monoblast = monocyte/macrophage precursor
- Blasts with megakaryocytic differentiation
- –> often with marrow fibrosis - Blasts with erythroid differentiation
Classification of AML
Subclassified based on cytogenetic abnormalities, lineage of myeloblasts and surface markers
4 categories:
- AML with genetic aberrations
- AML with myelodysplastic like features
- AML that is therapy related –> follow alkylation therapy, radiation therapy and topoisomeras inhibitor therapy; very poor outcomes
- AML, not otherwise specified
Acute promyelocytic leukemia (APL)
Characterized by t(15:17)(q22;11-12) = RAR/PML –> involves translocation of the retinoic acid receptor (RAR) on chromosome 17 to chromosome 15
- RAR disruption blocks maturation and promyelocytes accumulate
- abnormal promyelocytes contain numerous granules that increase the risk for DIC
- treatment with all trans retinoic acid (ATRA = a vit A derivative) –> binds the altered receptor and causes the blasts to mature
Morphology:
- M3 - promyelocytes
- large, often bilobed nuclei
- azurophilic cytoplasmic granules
- auer rods –> not totally specific
Chronic Myeloid Leukemia (CML)
Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors
- form of myeloproliferative disorder
- basophils are characteristically increased
characterized by t(9;22) = philadelphia chromosome –> generates a BCR-ABL fusion protein with increased TK activity
- also inhibits DNA repair –> leads to decreased genetic stability
- first line tx = imatinib –> blocks TK activity
CML morphology
Hypercellular marrow with overgrowth of maturing granulocytes
- includes elevated eosinophils and basophils
- megakaryocytes are usually increased but dysplastic
- erythroids usually normal/decreased
- “sea-blue” histiocytes
Peripheral blood with increased myeloid cells at varying degrees of maturation
- less than 10% blasts
Splenomegaly is common
CML progression
Typically a latent period (even without therapy, may last several years)
~50% enter accelerated phase with 10-19% blasts (also other criteria) - Worsening anemia/thrombocytopenia - Accumulating cytogenetic abnormalities - Eventually enters blast crisis
~50% enter blast crisis directly
- Resembles acute leukemia, but will have persistent BCR-ABL
- > 20% blasts &/or large clusters of blasts in marrow &/or solid focus of blasts outside of marrow (aka chloroma)
Lymphoid leukemias
- Derived from lymphoid precursors
- May often behave more like a lymphoma
- Terminology is ‘leukemia/lymphoma’
- May be acute or chronic (ALL or CLL)
Acute lymphoblastic leukemia (ALL)
Neoplastic accumulation of lymphoblasts in the bone marrow (>20%)
- Majority (~85%) are B-ALL
- ALL is most common cancer of children, and most ALL cases occur in children
- Associated with Down syndrome, usually arises after 5 years of age
- B- and T-ALL is morphologically similar
ALL morphology
B-ALL: usually leukemic presentation
- Lymphoblasts filling the marrow
T-ALL: usually lymphomatous presentation
- Mediastinal mass (+/- lymphadenopathy, splenomegaly)
Large nuclei, scant cytoplasm (high N:C ratio)
High mitotic rate
- High apoptotic rate ‘starry sky’
ALL diagnosis
Definite diagnosis depends on additional testing
- differential = ALL vs. AML
- then B-ALL vs. T-ALL
Terminal deoxynucleotidyl transferase (TdT) characterizes it as ALL
B cell vs. T cell markers subclassify
- B-ALL —> CD10, CD19 + CD20
- T-ALL –> CD2-CD8
ALL - chromosomal changes
90% with chromosomal abnormalities
B-ALL
- Hyperdiploidy
- Hypodiploidy
- Balanced translocation
- –> t(9;22)- Philadelphia chromosome = poor prognosis, more commonly seen in adults
- –> t(12;21) = Better prognosis, more commonly seen in children
T-ALL
- NOTCH1
- Translocation of alpha-delta, beta, gamma receptor loci
Small lymphocytic lymphoma
Chronic lymphocytic leukemia
CLL = Neoplastic proliferation of naive B cells –> most common leukemia overall
Involvement of lymph nodes leads to generalized lymphadenopathy –> called small lymphocytic lymphoma
- Older adults
- Typically indolent disease, but may undergo transformation
- –> Prolymphocytic
- –> Diffuse large B-cell lymphoma
Morphology:
- involvement of nodes, liver, spleen, marrow and blood
- increased lymphocytes and smudge cells are seen on blood smear
- small lymphocytes –> proliferation centers (pseudofollicles) are pathognomonic
Immuno and Molecular
- Mature B cell markers and surface Ig –> CD5, CD19, CD23
- chromosomal translocations are rare
- deletions and trisomies are more common
Myelodysplastic syndromes
Clonal populations with defective maturation
- often with chromosomal abnormalities –> monosomies, deletions, trisomies
- may be primary or secondary to therapy
- high rate of progression to AML
Morphology
- marrow usually hypercellular, but may be normo or hypocellular
- dysplastic differentiation of all lineages –> may be different degrees of involvement
Myeloproliferative disorders/neoplasms
Neoplastic proliferation of mature cells of myeloid lineage –> result in high WBC count with hypercellular bone marrow
- cell of all myeloid lineages are increased –> classified based on the dominant myeloid cell produced
- increased proliferation in marrow and in secondary hematopoietic organs
Common pathogenesis - activating mutation of TKs
- activate growth/survival
- do not alter differentiation –> increased numbers of mature blood cells
Complications
- increased risk for hyperuricemia and gout due to high turnover of cells
- progression to marrow fibrosis and cytopenias = spent phase
- transformation to acute leukemia
Polycythemia Vera
Neoplastic proliferation of mature myeloid cells, especially RBCs
- granulocytes and platelets are also increased
- associated with JAK2 mutation
- ~20% of patients progress over time to spent phase = marrow fibrosis, splenomegaly due to extramedullary hematopoiesis
- very rare progression to AML
Clinical symptoms of polycythemia vera
Mostly due to hyperviscosity of blood
- blurry vision and headache
- increased risk of venous thrombosis
- flushed face due to congestion
- itching, especially after bathing –> due to histamine release from increased mast cells
Essential thrombocytosis
Neoplastic proliferation of mature myeloid cells, especially platelets
- RBCs and granulocytes are also increased
- associated with JAK2 mutation
Symptoms related to an increased risk of bleeding and/or thrombosis
- rarely progresses to marrow fibrosis or acute leukemia
- no significant risk for hyperuricemia or gout
- extramedually hematopoeisis + organomegaly in ~50%
Differential diagnosis
- PCV –> absence of polycythemia
- PMF –> absence of marrow fibrosis
Essential thrombocytosis morphology
- normocellular/mildly hypercellular marrow
- markedly increased megakaryocytes –> may be atypically large
- lack of true fibrosis
- peripheral blood with increased and atypically large platelets
Primary myelofibrosis
Replacement of marrow space by fibrosis, without a preceding myeloproliferative disorder
- JAK2 50-60
Morphology
- early phase may resemble PCV –> lacks criteria of erythroid mass/hct for PCG; only presents in this phase in ~30% of cases
- progressive fibrosis with crowding out of marrow elements –> premature forms will be released into blood; bone marrow space may subsequently ossify
- extramedullary hematopoiesis
Difference between myelodysplastic syndromes and myeloproliferative syndromes
Myelodysplastic syndromes
- abnormal maturation
- relatively high rate of progression to AML
Myeloproliferative syndromes
- normal maturation
