Introduction to Hematologic Neoplasms; Acute Leukemias

Hematologic Neoplasms

They were the first human cancers in which a consistent genetic defect was identified.

Leukemia

Is derived from the ancient Greek words leukos, meaning "white", and haima, meaning "blood".

Hematologic Neoplasms

Terms that refer to large heterogeneous groups of disorders; they initiate in a hematopoietic cell as a result of acquisition of one or more mutations in key genes that regulate cell growth (proliferation), survival, differentiation, or maturation.

Leukemia

Originate in bone marrow, and ____ cells readily pass into peripheral blood, but they can also infiltrate lymphoid tissues (spleen, liver, lymph nodes) as well as other organs and tissues of the body.

Leukemia

Are divided into lymphoid and myeloid lineages, and further into acute (precursor cell) and chronic (mature cell) categories.

Acute Leukemias

Onset is sudden, progression is rapid, and the outcome is fatal in weeks or months if left untreated.

Acute Leukemias

White blood cell (WBC) count is variable, and there is an excess accumulation of precursor hematopoietic cells or blasts of a specific lineage in bone marrow and peripheral blood because of a block in differentiation (maturation arrest).

Chronic Leukemias

Onset is insidious and progression is lower, with a longer survival compared with acute leukemia.

Chronic Leukemias

The WBC count is usually elevated, and there is a proliferation and accumulation of mature and maturing cells of a specific lineage.

Lymphoma

Solid tumors of lymphoid cells that usually originate in the lymphatic system and proliferate in lymph nodes and other lymphoid organs and tissues.

Myeloma (Plasma Cell Neoplasms)

Cancer of the plasma cells; in ______, the cells overgrow, forming a mass or tumor that is located in the bone marrow.

Myelodysplastic Syndromes (MDS)

Group of acquired clonal hematologic disorders characterized by progressive cytopenias in the peripheral blood, reflecting defects in erythroid, myeloid, and/or megakaryocytic maturation.

Acute Leukemias

Refers to the rapid, clonal proliferation in the bone marrow of lymphoid or myeloid progenitor cells known as lymphoblasts and myeloblasts.

FAB Classification

Classification scheme for acute leukemias that is devised in the 1970s. Based on bone marrow morphology, cytochemical reactions, cytogenetics, and immunophenotyping.

FAB Classification

Criteria for diagnosis of acute leukemia is >30% of blasts in the blood is associated with leukemia.

WHO Classification

Classification scheme for acute leukemias that is the gold standard in classifying leukemias.

FAB Classification

Classification scheme for acute leukemias that is based on bone marrow morphology, cytochemical reactions, cytogenetics, and immunophenotyping.

WHO Classification

Classification scheme for acute leukemias that is based on bone marrow morphology, cytochemical reactions, immunophenotyping, clinical manifestations, cytogenetics (detection of the abnormal gene)>

WHO Classification

Criteria for diagnosis of acute leukemia is >20% of blasts in the blood is associated with leukemia.

Acute Lymphoblastic Leukemia (ALL)

Is primarily a disease of childhood and adolescence, accounting for 25% of childhood cancers and up to 75% of childhood leukemia (most common type of leukemia in the children).

Acute Lymphoblastic Leukemia (ALL)

Its peak incidence in children is between 2 and 5 years of age; although it is rare in adults, risk increases with age; most adult patients are older than 50 years of age.

Acute Lymphoblastic Leukemia (ALL)

Its subtype is an important prognostic indicator for survival; adults have a poorer outlook: 80% to 90% experience complete remission, but the cure rate is less than 40%.

Acute Lymphoblastic Leukemia (ALL)

Lymphoblasts stain PAS and TdT positive; Sudan Black B (SBB) and Myeloperoxidase (MPO) negative.

Acute Lymphoblastic Leukemia (ALL)

Laboratory Findings:

- WBC count of >50 x 10^9/L; less than 15% of patients have extreme leukocytosis (WBC count of >100 x 10^9/L)

- Predominance of blasts cells (>20% for WHO; >30% for FAB) in about 50% of patients (lymphoblasts with lymphocytes and smudge cells)

- Granulocytopenia

B-Lymphoblastic Leukemia/Lymphoma (B-ALL)

WHO classification of ALL; Is subdivided into nine subtypes that are associated with recurrent cytogenetic abnormalities.

T-Lymphoblastic Leukemia/Lymphoma (T-ALL)

WHO classification of ALL; Have abnormal gene rearrangements, none of the abnormalities is clearly associated with specific biologic features.

FAB L1

FAB classification of ALL; children.

FAB L2

FAB classification of ALL; older children and adults.

FAB L3

FAB classification of ALL; patients with leukemia secondary to Burkitt's lymphoma; t(8;14) -> myc oncogene.

Small Lymphoblast

The most common type seen is a _______ (1.0 to 2.5 times the size of a normal lymphocyte) with scant blue cytoplasm and indistinct nucleoli.

Larger

The second type of lymphoblast is ______ (two to three times the size of a lymphocyte) with a prominent nucleoli and nuclear membrane irregularities; these cells may be confused with the blasts of AML.

Immunophenotyping and Genetic Analysis

Although morphology is the first tool used to distinguish ALL from AML, ___________ are the most reliable indicators of a cell's origin.

Early B-cell ALL (Pro-B or Pre-pre B cell ALL)

In immunophenotyping, it is seen in 5% in children and 11% in adults.

Intermediate (Common) B-cell ALL

In immunophenotyping, t(4;11), CD10 (CALLA -> Common ALL antigen).

Pre-B cell ALL

In immunophenotyping, t(9;22) -> Philadelphia chromosome. Most mature B cell ALL; TdT negative, CD34 variable.

Pre-B cell ALL

In immunophenotyping, it is seen in 15% of childhood and 10% of adult B cell ALL.

T cell ALL

In immunophenotyping, t(7;11). Most often in teenaged males with a mediastinal mass, elevated peripheral blasts counts, meningeal involvement, and infiltration of extra marrow sites.

Acute Myeloid Leukemia (AML)

Is the most common type of leukemia in adults, and the incidence increases with age. Less common in children.

FAB

_____ classification of AML was based on morphology and cytochemistry.

WHO

_____ classification of AML relies heavily on molecular characterization and cytogenetics.

Acute Myeloid Leukemia (AML)

Laboratory Findings:

- Decreased production of normal bone marrow elements

- WBC count: 5-30 x 10^9/L

- Myeloblasts (>20% for WHO; >30% for FAB) are present in the peripheral blood in 90% of patients.

- Anemia, thrombocytopenia, and neutropenia

Acute Myeloid Leukemia (AML), Minimally Differentiated (FAB M0)

FAB classification that accounts for less than 5% of AML, and patients are generally either infants or older adults.

Acute Myeloid Leukemia (AML), Minimally Differentiated (FAB M0)

FAB classification in AML which Auer rods typically are absent, and there is no clear evidence of cellular maturation. Markers present: CD13, CD33, CD34, CD117

Acute Myeloid Leukemia (AML), Minimally Differentiated (FAB M0)

FAB classification in AML which cells yield negative results with the cytochemical stains myeloperoxidase (MPO) and Sudan Black B (SBB).

Acute Myeloid Leukemia (AML), Without Maturation (FAB M1)

FAB classification in AML that may comprise >90% myeloblasts, and fewer than 10% of the leukocytes show maturation to the promyelocyte stage or beyond.

Acute Myeloid Leukemia (AML), Without Maturation (FAB M1)

FAB classification in AML that has at least 3% of blasts give positive results with myeloperoxidase (MPO) or Sudan Black B (SBB) stains; also stain with CAE.

Acute Myeloid Leukemia (AML), Without Maturation (FAB M1)

Markers present are CD13, CD33, CD117, CD34

Acute Myeloid Leukemia (AML), Without Maturation (FAB M1)

FAB classification in AML that has presence of chloroma -> green appearance of tissue using MPO. Auer rods may be present.

Acute Myeloid Leukemia (AML), With Maturation (FAB M2)

FAB classification in AML that is similar to t(8;21)(q22;q22.1); RUNX1/RUNX1T1 mutation in WHO classification.

Acute Myeloid Leukemia (AML), With Maturation (FAB M2)

FAB classification in AML which is the common variant that presents with <90% myeloblasts and >10% maturing cells of neutrophil lineage, and <20% precursors with monocytic lineage.

Acute Myeloid Leukemia (AML), With Maturation (FAB M2)

FAB classification in AML wherein auer rods are often present. Most blasts stain with MPO, SBB, and CAE. Markers present are CD13, CD33, CD117, CD34.

FAB M1 and M2

Account for 50% of AML cases.

Acute Promyelocytic Leukemia (FAB M3)

Comprises 5% to 10% of AML cases; occurs in all age groups but is seen most commonly in young adults.

Acute Promyelocytic Leukemia (FAB M3)

Characterized by a differentiation block at the promyelocytic stage.

Acute Promyelocytic Leukemia (FAB M3)

The presence of >30% abnormal promyelocytes with bundles of Auer rods (f4ggot cells).

Hypergranular

Abnormal promyelocytes that is associated with DIC and absence of HLA.

Hypogranular/Microgranular

Abnormal promyelocyte; aPML-M3v; 20-30% of APL cases; presence of "butterfly" or coin-on-coin nucleus.

Acute Promyelocytic Leukemia (FAB M3)

Cytogenetic abnormality involves balanced translocation between chromosomes 15 and 17 t(15;17); fusion of PML gene and retinotic acid receptor alpha (RARa) or the PML-RARa gene.

PML-RARa

95% of APL cases have the ________ protein.

Acute Promyelocytic Leukemia (FAB M3)

Treated with all-trans-retinoic acid (ATRA) and arsenic trioxide.

Acute Myelomonocytic Leukemia (FAB M4)

Characterized by a significantly elevated WBC count and the presence of myeloid and monocytoid cells in the peripheral blood and bone marrow.

Acute Myelomonocytic Leukemia (FAB M4)

Characterized by >20% (WHO) or >30% (FAB) marrow myeloblasts with >20-80% cells of monocytic origin (monoblast, promonocyte, monocyte); may have Auer rods.

Acute Myelomonocytic Leukemia (FAB M4)

Also called as Naegeli's type; accounts for 30% of AML cases.

FAB M4Eo

Variant of FAB M4 with myeloblasts and monoblasts along with abnormal eosinophils.

Acute Monocytic Leukemia (FAB M5)

Characterized by >20% (WHO) or >30% (FAB) marrow monoblasts; account for 10% of AML cases.

Acute Monocytic Leukemia (FAB M5)

In these leukemias, which are divided into monoblastic (M5a) and monocytic (M5b) based on the degree of maturity of the monocytic cells present.

Acute Monocytic Leukemia (FAB M5)

Cytogenetic abnormality: t(8;16)(p11;p13) has been associated with M5 (also M4).

Acute Monocytic Leukemia (FAB M5)

Markers present are CD14, CD4, CD11b, CD11c, and CD64. Cells stain positive with NSE.

Acute Erythroleukemia (FAB M6)

One of the major changes in the 2017 WHO classification is the removal of acute erythroleukemia (erythroid/myeloid type) - most of these cases will now be classified as MDS with excess blasts.

Acute Erythroleukemia

AKA Erythemic Myelosis, or Di Guglielmo's Syndrome.

Acute Erythroleukemia

Characterized by >20% (WHO) or >30% (FAB) marrow myeloblasts and >50% dysplastic marrow normoblasts/erythroblasts.

Acute Erythroleukemia

Myeloblasts stain positive with SBB, MPO, CAE; erythroid cells are PAS Positive.

Pure Erythroid Leukemia

Remains as M6; characterized by >80% erythroid cells; >30% proerythroblasts.

Pure Erythroid Leukemia

RBC precursors have significant dysplastic features; presence of ringed sideroblasts, Howell-Jolly bodies and other inclusions.

Acute Megakaryoblastic Leukemia (FAB M7)

Characterized by the presence of at least >20% (WHO) or >30% (FAB) blasts, of which at least 50% must be of megakaryocyte origin; rarest type of AML.

Acute Megakaryoblastic Leukemia (FAB M7)

Cells are stained with Alpha Naphthyl Acetate Esterase (ANAE) and PAS.

Acute Megakaryoblastic Leukemia (FAB M7)

Markers present are von Willebrand factor, CD41 (gp IIb), CD42b (gp Ib), CD61 (gp IIIa).