Diagnosing Acute Myelogenous Leukemia (AML)

The "latency period" for benzene-induced leukemias can range anywhere from less than a year to 40 or more years after first exposure.

High Risk Occupations

The "Latency period" refers to the period of time between initial exposure to a toxic chemical and the onset of symptoms from a diagnosed cancer. For example, the typical latency period for malignant mesothelioma, a tumor caused by exposure to asbestos, is between 15 and 40 years. That means that the typical interval between initial exposure and the development of a tumor is 15 to 40 years.

Benzene-induced leukemias can have a much shorter latency period when compared to asbestos and other carcinogens. There are reports of benzene-induced leukemias being diagnosed in patients only 8-9 months following their exposure to benzene. However, there are also reports of benzene-induced leukemias being diagnosed 40 or more years after initial exposure. Accordingly, the determination of whether a patient's leukemia was caused by exposure to benzene should involve a thoughtful consideration of any and all exposures to benzene or benzene-containing products during as many as 50 years preceding the diagnosis.

The symptoms of leukemia and related bone marrow disorders are parallel to many other diseases. During medical evaluation the physician will ask a number of questions regarding recent and previous illnesses. If signs and symptoms suggest acute myelogenous leukemia (AML), sample cells will be taken from blood and bone marrow for laboratory testing.

A number of specialized physicians, including a pathologist, an expert in disease diagnosis, and a blood specialist known as a hematologist will work together to confirm the AML diagnosis.

Blood Test

Bone Marrow Aspiration and Biopsy

Cytology

Immunophenotyping

Cytochemistry

Flow Cytometry

Cytogenetics

Other Diagnostic Testing

What is a “Blast” and What is its Diagnostic Significance?

Staging

Types & Subtypes of Leukemia

What are clinical biomarkers?

How Benzene is Metabolized by the Body

Use of White Blood Cell Counts for Occupational Screening

Suppression of Absolute Lymphocyte Count

Acute vs. Chronic Leukemia

Comparison of Acute versus Chronic Leukemia

Sources

Blood Test [Top]

A full blood count (FBC) or complete blood count (CBC) is the test that provides all the cell information about your blood.

Two different counting methods will likely be used. Either an automated analyzer or a hematology analyzer (a cell counter) will provide a very precise measurement of normal cell levels. However, abnormal cells may be identified incorrectly by both methods

A second count is manually performed to identify the number of blasts, prematurely released white blood cells, that are in a patient's blood

Bone Marrow Aspiration and Biopsy [Top]

Patients with AML have low levels of red blood cells (erythrocytes), low levels of platelets (thrombocytes), and high levels of white blood cells (leukocytes) in their blood. When a high number of white blood cells or blasts are found, a confirmed diagnosis of AML can only be obtained through a sample of the bone marrow.
Bone marrow aspiration and biopsy procedures are more invasive and may require pain killers to ease the discomfort.

A bone marrow aspiration is a procedure where approximately one teaspoon amount of bone marrow liquid is suctioned from the back of the pelvic or hip bone.

A second specimen, an estimated 1/16 inch cylindrical section of the bone marrow is harvested from the same site and contains a solid piece of bone and marrow. This is known as a core biopsy.

The bone marrow cells are evaluated according to their size, shape, granule(s) content and maturity.

The mature cells are normal cells found in the circulating blood which actively fight infection but can no longer reproduce.

Immature cells are undeveloped blood cells and poor infection fighters but are capable of reproduction. These are known as 'blasts'.

Blasts percentages found in those with AML can escalate from 30 to 95 percent.

Cytology [Top]

Cytology is the examination of the peripheral blood (PB) and bone marrow (BM) films by microscope.

Cytologists use the traditional Romanowsky-stained techniques as the standard for hematology diagnosis.

Immunophenotyping [Top]

Immunophenotyping can determine at which stage of development the cell became leukemic.

By testing for surface cell markers produced by each specific type of leukemia the 7 subtypes of AML can be identified and classified.

Immunophenotypic analysis will establish if the blasts are myeloid or lymphoid.

Blasts identified as myeloid return a diagnosis of AML.

The diagnostic accuracy achieved by immunophenotyping is a valuable tool for developing a treatment program.

Cytochemistry [Top]

Cytochemistry is the branch of biochemistry that studies the chemical composition and activity of cells.

Special chemical stains (dyes) are used on the cells from the original sample and when applied the chemical stains cause the granules of most AML cells to appear black in color or as black spots when observed through the microscope.

The essential cytochemical tests are: myeloeroxidase (MPO) or Sudan black B (SBB); non-specific esterase (NSE); or combined esterase (CE); and, Perls’ stain. http://pathologyoutlines.com/stainspf.html

Flow Cytometry [Top]

Flow Cytometery is another accurate technique used to determine the exact type of leukemia a patient has.

Special antibodies applied to the sample cells are passed in front of a laser beam.

The laser will cause antibodies attached to the surface molecules to give off light, which is measured and analyzed by the computer.

This method will allow groups of cells to be separated and counted.

Flow Cytometry is used to obtain an Absolute Lymphocyte Count (ALC) of white blood cells, lymphocytes and T cells. ALC recovery serves as a powerful predictor for survival of post-autologous stem cell transplantation Studies are being conducted to determine if ALC can determine the prognosis and survival rate of patients after induction chemotherapy

Cytogenetics [Top]

Cytogenetics is the study of chromosomes. Cytogenetic testing explores the causes of abnormalities in the chromosomes.

Cytogenetics, the microscopic study of chromosomes, requires expert analysis and identification of specific chromosomal abnormalities as it is used increasingly to decide treatment.

Chromosomes contain DNA that control metabolism and cell growth.

Patients initially diagnosed with AML should have cytogenetic testing done to analyze damage to chromosomes.

Patients with acute leukemia in remission will not benefit from cytogenetic analysis because the procedure cannot adequately detect low levels of the clone.

In some types of leukemia, two chromosomes may exchange or attach some of their DNA to the other chromosome. This is known as translocation (i.e. part of chromosome #1 is now located on chromosome #2).

Other chromosome changes are inversions, deletions, and additions.

Other Diagnostic Testing [Top]

FISH (fluorescent in situ hybridization) is a sophisticated test which aides in the molecular genetic detection of translocations not seen under a microscope of many subtypes of AML.

Gene-Expression Profiling is a experimental technique that creates a fingerprint for some cancers but it is used to classify the various types of AML into particular risk categories.

Imaging Studies (pictures of the inside of the body) are done when AML patients have infections or medical problems not associated with their cancer.

X-rays, CT scans, MRI(s), Gallium scan or bone scan and ultrasound are also used by treating physicians.

What is a “Blast” [Top]

Stedman’s Medical Dictionary defines “Blast” as an immature, embryonic stage in the development of cells or tissues.

When “Blast” is generically stated in diagnosing AML the writer is referring to a “Blast Cell”, an immature precursor of a blood cell.

The healthy, normal bone yields less than 5 percent of blast cells.

If the percentage of blasts found in the bone marrow is at least 20%, the pathologist will likely return a diagnosis of acute myeloid leukemia.

The characteristics of blast cells in a patient play an important role in diagnosing the correct leukemia subtype and AML sub-classification

Staging [Top]

Staging is used in most cancers to chart the course of the disease according to the extent of the tumor. Because, leukemia normally spreads before it is detected the disease is described as “untreated,” in “remission,” or “recurrent.”

Cell classification systems are relied upon to identify the type and subtype of leukemia. This system helps predict the prognosis and the probable response to treatment of specific forms of leukemia.

Types & Subtypes of Leukemia [Top]

The two classifications of leukemia are based on the cell type; myeloid and lymphoid.

Clinical behavior of the disease determines if leukemia is acute or chronic and myelogenous versus lymphocytic.

For more than 20 years the French-American British (FAB) has been the standard classification for leukemia; based on the cell morphology on May-Grunwald-Giemsa (MGG) staining of peripheral blood and bone marrow smears and basic cytochemical techniques.

The eight (8) subtypes of Acute Myelogenous Leukemia (AML) are:

  1. undifferentiated AML (M0)
  2. myeloblastic leukemia (M1)
  3. myeloblastic leukemia (M2)
  4. promyelocytic leukemia (M3 or M3 variant [M3V])
  5. myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E])
  6. monocytic leukemia (M5)
  7. erythroleukemia (M6)
  8. megakaryoblastic leukemia (M7)

The World Health Organization (WHO) recommends the clinico-biological classification of acute myeloid leukemia (AML) should include morphological, cytochemical, cytogentic, immunophenotypic and molecular characterization of the leukemia blasts.

Based on available data WHO suggests classifying AML into four main groups:

  1. AML with recurrent cytogenetic translocations
  2. mAML: Multilineage AML
  3. Secondary AML
  4. Morpholocical and Immunophenotyping classification (necessary for those that do not fit within the preceding categories)

Using these homogeneous categories (as explained in the Glossary section) would allow for further development and refinement of current and future treatment strategies.

What are clinical biomarkers? [Top]

Biomarkers are clinical tests that are specific to an occupational or environmental exposure or illness. In 1982, biomarkers were defined by The National Research Council, with respect to their clinical utility as follows:

EXPOSURE biological markers reflect an exogenous substance or its metabolite that is measured in a compartment of the body

Biological markers of EFFECT refer to the measurable alterations that can be seen as established or potential health impairment.

SUSCEPTIBILITY biological markers gauges a person’s ability to respond to an xemobiotic (foreign substance) challenge.

How Benzene is Metabolized by the Body [Top]

Benzene is metabolized by the body via two different pathways; inhalation and skin absorption.

The complete metabolism of benzene takes hours after its entry into the body via an inhalation exposure route.

Urinary products are normally eliminated rapidly.

Occupational exposure levels have a third, more slowly exchanging section.

Benzene is present in the blood and expired in the breath for extended time periods.

Use of White Blood Cell Counts for Occupational Screening [Top]

The minimum mandatory observations to be made from a peripheral blood smear are (1) differential white blood cell count; (2) description of the appearance of abnormalities in the red blood cells; (3) platelets abnormalities charted; and (4) thorough search of each blood smear for immature white cells.

Unexplained elevations of white blood cells are regarded as evidence of benzene exposure and the employee must immediately vacate the work area to prevent any further exposure to benzene vapor.

Suppression of Absolute Lymphocyte Count [Top]

Lymphocytes are any one of a group of white blood cells that are crucial to the body’s immune system. Some of them are known as B-cells and T-cells.

The T-lymphocytes in a donor’s bone marrow or blood can cause a harmful reaction known as graft versus host disease.

Prior to transplant the collection of marrow or blood can be treated with agents that will decrease the number of T-lymphocytes that are to be infused with the stem cells.

Acute vs. Chronic Leukemia [Top]

While both Acute and Chronic Leukemia are usually cancers of the white blood cells, the distinction between them is based upon their "untreated" behavior.

Acute leukemia affects growing cells very early in cell life causing the cells to remain immature and unable to function. Patients with acute leukemia are more likely to suffer from infection, bleeding and anemia. Acute leukemia can be fatal within months if immediate treatment is not pursued.

Chronic leukemia affects the more mature cells which can retain much of their normal function. The chance of bleeding and infection are less likely and patients may live for many years without treatment.
A chronic leukemia can sometimes convert to an acute variety known as Richter’s syndrome.

Comparison of Acute versus Chronic Leukemia [Top]

Statistical Data Acute Chronic
Age Individuals in their 40's,50's, 60's First and second decades -youth
Sex

Male: 2 / Female: 1

 Male: 1 / Female: 1
Duration Weeks to months Several months to one year
Presenting complaints Anemia; Fever; infections, weight loss

Haemorrhagic tendencies
Neurological complications
Blood Count Leuccocyte count moderately elevated

Leuccocyte count grossly elevated
Chromosomal studies

Variable

 Philadelphia chromosome 90-95%
Course / Prognosis

Untreated – fatal weeks to 6 months

 Untreated – median survival of 18 – 24 months
Response to treatment

90% remission; 60 – 70% cure

Bone marrow cure rate exceed 50%; chemotherapy – no cure

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