ACUTE LEUKEMIA OVERVIEW

The acute leukemias are characterized by aberrant differentiation and proliferation of malignantly transformed stem cells in the bone marrow.

The bone marrow is the spongy tissue where blood cell development takes place. The process of blood cell development is referred to as hematopoiesis.


As blood cells mature, they differentiate into cells with specific duties within the body such as transporting oxygen, and fighting infections.

After blood cells mature, grow and develop in the bone marrow, they migrate from the marrow to the blood stream.

In the setting of acute leukemia, aberrant cells accumulate within the bone marrow leading to the suppression in growth of the normal blood cells. The acute leukemias are classified as lymphoid or myeloid, depending on the cell line involved in the malignant transformation. They are further classified based on their immunophenotype and genotype.

After a diagnosis of leukemia is confirmed it is assigned a sub-classification by immunotype, genotype (evaluating the chromosomes) and FAB (French American and British), which dictates the further therapy. The sub-classification of the disease is imperative given that different sub types have different prognoses and different courses of therapy.

ACUTE MYELOGENOUS LEUKEMIA (AML)

Acute Myelogenous Leukemia (AML) is also known as acute nonlymphocytic leukemia. Usually patients who present with AML require immediate therapy for their disease and may already have an infection or bleeding complication at the time of diagnosis.

Acute Myelogenous Leukemia is classified according to the FAB (French, American and British) Classification system. The FAB classification system for acute leukemia and myelodysplasia, was originally based on cytomorphology and cytochemical findings. It was created to establish a universal system for nomenclature, diagnosis and classification of acute leukemia, and is still widely used.

M0 - Undifferentiated (AUL)
M1 - Myeloblastic without differentiation
M2 - Myeloblastic with maturation
M3 - Promyelocytic (APL)
M4 - Myelomonocytic (AMMoL)
M5 - Myeloblastic/Monocytic (AMoL)
M6 - Erythroleukemia (AEL)
M7 - Megakaryocytic leukemia (AMegL)
ACUTE LYMPHOBLASTIC LEUKEMIA

Acute lymphoblastic leukemia (ALL), also referred to as acute lymphocytic leukemia, is the most common leukemia diagnosis in children. However it accounts for only 20% of all new leukemia diagnoses in adults.

In ALL, there is a proliferation of immature lymphoid precursor cells. In normal cell differentiation, lymphoid stem cells develop into either B or T cell lymphoblasts which further develop into mature B or T cell lymphoctyes which have specific immune system functions.

In ALL, however, immature lymphoid cells fail to progress beyond the lymphoid blast or lymphoblast development stage. These immature cells, incapable of doing the immune system work of mature cells, build up in the bone marrow crowding out the healthy cells.

B-cell ALL is the most common type in adults.

ALL is classified as follows:

Immunophenotype (such as common Acute Lymphocytic Leukemia Antigen calla) The immunophenotype is determined through a test that looks at the reaction of antibodies with antigens to determine specific types of cell(s) in blood, bone marrow, or lymph nodes.
Genotype (such as Philadelphia chromosome (see below)
FAB subgroup The three FAB ALL types (British J Haematology, 33:451-458, 1975) while still in use have largely been replaced by immunologic classification.
These sub classifications carry significant prognostic value. To confirm a diagnosis and accurately treat a person with ALL, a spinal tap often is performed at the time of initial work up.


Subtypes of Acute Lymphocytic Leukemia:

Microscopic Features
Microscopic features are summarized by classifying the cells as L1 (small), L2 (large), L3 (large with other features).

Immunophenotypes
B lymphocytic lineage subtypes. These cases are identified by finding cell surface markers on the leukemic blast cells that are identical to those that develop on normal B lymphocytes. About 85 percent of cases are of the B cell subtype.

T lymphocytic lineage subtypes. These cases are identified by finding cell surface markers on the leukemic blast cells that are identical to those that develop in normal T lymphocytes. About 15 percent of cases are of the T cell subtype.

Other surface or cell markers are considered as well. (e.g., common Acute Lymphocytic Leukemia antigen or cALLa).

Chromosome Abnormalities
Injury to chromosomes can be assessed by cytogenetic methods, and the specific alteration in chromosomes aids in subclassifying acute lymphocytic leukemia, also. For example, a change in chromosome number 22, referred to as the Philadelphia or Ph chromosome, which occurs in a small percentage of children and a larger percentage of adults with acute lympohcytic leukemia, places the patient in a highter risk category. Thus, the approach to therapy would be intensified in those subsets of patients.

CHRONIC MYELOID LEUKEMIAS (CML)

The chronic myeloid leukemias are part of the group of diseases known as the myeloproliferative blood disorders. They have been recognized as distinct clinical entities separate from the broad classification of leukemia only within the last 25 years. The chronic leukemias are classified as myeloid or lymphoid depending on what cell line is affected by the malignant transformation.

Philadelphia Chromosome

Normal human cells have a total of 46 chromosomes, that are composed of 22 pairs including the two sex chromosomes ( XY in males, and XX in females). In CML patients, chromosomes #9 and #22 have swapped some genetic material. This chromosomal abnormality is called Philadelphia Chromosome after the researchers at the University of Pennsylvania who discovered it. The Philadelphia Chromosome has become the hallmark sign of CML.

In addition, during the progressive malignant evolution of CML, other cytogenetic changes may develop, such as trisomy 8, double Philadelphia chromosomes, and isochromosome 17. The abnormalities in these chromosomes lead to the progressive replacement of the normal cells in the marrow. The leukemia cells coexist with the healthy cells in the marrow. The ratio of leukemia cells to normal cells eventually increases to where the leukemia cells are crowding out the healthy cells, and therefore the healthy cells are not able to carry out their jobs effectively such as fighting infections, and prevent bleeding.

CML Phases

Chronic Myelogenous Leukemia is broken down into specific phases. A persons phase is determined by bone marrow, peripheral blood and cytogenetic findings, at the time of diagnosis. A persons phase and other presenting features at diagnosis carry prognostic significance and may assist in determining front line treatment.

The phases of CML are classified as chronic phase, accelerated phase, and blastic phase (sometimes referred to as blast crisis). Patients are most often diagnosed in the chronic phase of their disease. Chronic phase leukemia is more easily controlled with medications (chemotherapy) then the other stages of CML.
Phase of CML
Bone Marrow
and Blood Count
Findings
Average Age and Symptoms

Chronic Phase 20% or less immature cells in the blood.

5% or less blast cells in the bone marrow.
Median patient age 50 years old, effecting males slightly more then females.
Patients may complain of fatigue, malaise, headache, weight loss, abdominal discomfort (usually from an enlarged spleen).

Accelerated Phase Greater then 5% but less then 30% blasts in the blood and bone marrow.
Progressive systemic physical complaints. Patients usually anemic, and have many platelet abnormalities, which may result in bleeding problems.

Blastic Phase (Blast Crisis) 30% or more blasts in the blood and marrow.
Patients complain of fever, night sweats, weight loss, achy bone pains, weakness, and easy bruisability.





--------------------------------------------------------------------------------

The Role of the Pathologist

Lymphoma and leukemia are general categories that represent at least 30 types of cancer of the blood forming cells. The diagnosis is usually made by sampling a lymph node, bone marrow aspirate or biopsy or peripheral blood smear. Advances in research have determined that many types of lymphoma and leukemia respond best to specific treatment protocols. If the cancer gets an incorrect or inaccurate diagnosis, it is possible that the patient will receive inappropriate therapy. A number of sophisticated tests can be performed on the tissues to assist in determining the most accurate diagnosis. Tissue samples (biopsy) taken for the evaluation of lymphoma or leukemia should be examined by a hematopathologist, a pathologist with special training and expertise in these cancers.


Edited by Jaffar Qama Al-Hilly, MD, Director of the Pediatric Blood and Marrow Transplant Program, Experimental Therapeutics and Hematopoiesis, and Pediatric Cancer Research Program at the Columbia University Medical Center, Babies and Children Hospital.