ALL 3-7YEARS	AML ALL AGES	CML 50 YEARS	CLL 70 YEARS	HAIRY CELLS 50 YEARS
· FEVER · PETECHIAE · ECCHYMOSES · CNS INFILTRATE	· FEVER · PETECHIAE · ECCHYMOSES · LYMPHADENOPATHY [ SPLENOMEGALY]	· FEVER · NIGHT SWEATS · SPLENOMEGALY	· LOW IG LEVELS INFECTIONS	· HEPATOMEGALY · SPLENOMEGALY · TRAP
PROGNOSTIC: FAIR	POOR	POOR	FAIR	POOR
LYMPHOBLASTS	AUERS RODS IN MYELOBLASTS A/W IRRADIATION RADIATION THERAPY	PHILADELPHIA CHROMO IN MYELOID STEM CELLS T[9q-22q]	LYMPHOCYTES PREDOMINENCE	PANCYTOPENIA HAIRY CELLS IN BONE MARROW

Classification of AML
Type	FAB
Acute myeloid leukemia (Acute nonlymphocytic leukemia, ANLL)	AML
Acute myelocytic leukemia	AML-M1 AML-M2
Acute promyelocytic leukemia	AML-M3
Acute myelomonocytic leukemia	AML-M4,M4E
Acute monoblastic leukemia	AML-M5
Acute erythroleukemia	AML-M6
Megakaryoblastic leukemia	AML-M7

Development of the Myeloid Cell Line From the Pluripotent Stem Cell

• AML represents a block in myeloid differentiation and maturation and an increased proliferation of the blasts.
• The following growth factors play a role in the differentiation of normal hematopoietic cells:
• erythropoietin (EPO)
• thrombopoietin interleukin-1 (IL-1)
• interleukin-3 (IL-3)
• interleukin-5 (IL-5)
• interleukin-6 (IL-6)
• granulocyte-macrophage colony-stimulating factor (GM-CSF)
• granulocyte colony-stimulating factor (G-CSF)
• macrophage colony-stimulating factor (M-CSF)
• others
• As a result of chromosomal translocations, alterations in growth factor or growth factor receptorlsl functions may be key to the pathogenesis of AML.

Morphological Features of AML
TYPE(FAB)		CHARACTERISTIC MORPHOLOGY
Acute myelocytic leukemia (M1)		Cells very undifferentiated, occasionally cytoplasmic granules, some promyelocytes seen.
Acute myelocytic leukemia (M2)		Granulated blasts predominate, small number of monocytoid cells may be present, differentiation beyond promyelocytic stage evident, +/- Aeur bodies
Acute promyelocytic leukemia (M3)		Typically, hypergranular promyelocytes predominate, cells have large basophilic and esoinophilic granules, +/- Auder bodies
Acute myelomonocytic leukemia (M4)		Monocytic and granulocytic precursors seen, serum lysozyme elevated, +/- Auer bodies
Acute monoblastic leukemia (M5)		Large monoblasts with abundant, agranular cytoplasm that may be vacuolated and basophilic
Erythroleukemia (M6)		Megaloblastoid red cell precursors predominate, myeloid blasts also seen, multinucleated red cell precursors common
Megakaryocytic leukemia (M7)		Variable morphology, megakaryocytic features may not be seen with light microscopy
Histochemical Features of AML
FAB	HISTOCHEMISTRY
M1	Occasional peroxidate+ granules, PAS-
M2	Strongly peroxidase+, PAS-
M3	Strongly peroxidase+, PAS-
M4	Strongly peroxidase+, some cells may be PAS+
M5	Many be peroxidase+ and PAS+, nonspecific esterase stains are strongly + and inhibited by NAF
M6	Red cell precursors are PAS+, ringed sideroblasts are seen with iron stains
M7	Variable, platelet peroxidase can be demonstrated by electron microscopy

• Distinction among the various subgroups of AML is now possible with greater precision because of new histochemical studies and immunologic techniques.
• Immunophenotyping and terminal deoxytransferase (TDT) determination may help distinguish between AML and ALL, and between the various subtypes of AML

Peripheral Blood Features of AML

• The peripheral white blood cell count may be increased, decreased, or normal with approximately equal frequency.
• Granulocytopenia is very common. Approximately 1/2 of all patients will have granulocyte counts < 1,000/uL.
• Thrombocytopenia is frequently observed and platelet counts <20,000/uL are common.
• The hematocrit is generally low but severe anemia is uncommon.
• Circulating blast cells are absent from the peripheral blood in approximately 15% of AML patients initially, and in 1/2 of patients presenting with leukopenia.

Clinical Diagnostic Features of AML

• Adults with AML generally present with a vague history of chronic progressive lethargy; granulocytopenia and thrombocytopenia are common.
• The definitive diagnosis is made by examination of a bone marrow aspirate.
• As many as 1/3 of patients with AML will be acutely ill at presentation because of a significant skin, soft tissue, or respiratory infection.
• Petechiae with or without bleeding may be present. Patients with acute promyelocytic (M3) leukemia may have severe hemorrhaging secondary to a clotting factor deficiency, which results in an intravascular coagulopathy.
• Hyperuricemia is frequent; splenomegaly is present in about 1/3 of patients.
• Leukemias with a monocytic component (M4 & M5) may be associated with gingival hypertrophy from leukemia infiltration. Patients with these types of AML are most likely to present with or develop meningeal leukemia, retinal infiltration, leukemia cutis, or other localized leukemia infiltrations.
• Chloromas (granulocytic sarcomas, myeloblastomas) are present in about 5% of patients. They may take on a dull green color due to the high peroxidase content in the leukemia cell, may precede other diagnostic evidence, may occur aher diagnosis, or may indicate relapse. They commonly occur in the skin but can be present in other body organs. They are most ohen associated with M4 and M5 leukemias.
• Lymphadenopathy and hepatomegaly are uncommon. Increased intracranial pressure secondary to meningeal leukemia may rarely be present at presentation. Such patients usually have FAB M4 morphology and are usually young. In the absence of meningeal signs, a lumbar puncture is not indicated

Diagnostically Important AML Markers

· Morphologic

• Auer bodies
• "malignant" primary granules

· Cytoplasmic organelles

• chloracetate esterase
• Sudan B
• myeloperoxidase

· Cytogenetic

• t(8;21)
• t(15;17)
• -5,-7

· Immunologic/biochemical

• lysozyme
• cell surface markers

· A variety of morphologic, cytoplasmic, cytochemical, and biochemical features are associated with AML that can aid in diagnosis.

· No available marker is either totally specific or sensitive enough to be used in all cases.

· Cytogenetic analyses should be performed at diagnosis in all patients with AML. Approximately 65% of patients will have abnormal karyotypes.

· Cytogenetic abnormalities may help determine prognosis

Work-Up for Patient with AML

• Complete history:
• family, work, and medical history
• radiation and chemical exposure history
• Complete physical examination, with special attention to:
• temperature Iymph node-bearing areas and splenic
• area optic fundi and cranial nerves
• potential sites of infection:
• skin, including axillae
• oropharynx, including gingivae
• lungs
• perianal area
• Peripheral blood studies:
• hematocrit, leukocyte count, platelet count
• leukocyte differential count
• Bone marrow examination:
• perform biopsy to determine cellularity
• aspirate smears stained with Wright's, Sudan black, and esterase stains; periodic acid-Schiff reagent; iron stain; and immunofluorescent stain for terminal transferase
• aspirate for karyotyping and immunophenotyping
• Blood chemistries and other studies:
• serum electrolytes, uric acid, blood urea nitrogen, and muramidase (lysozyme)
• coagulation profile, including fibrinogen level, prothrombin time, and partial thromboplastin time
• liver function analysis
• Chest radiographs:
• chest posteroanterior and lateral radiographic films
• Transfusion work-up:
• determine blood type and human leulocyte antigen type if patient has circulating lymphocytes
• do same for family members who are willing to serve as platelet, granulocyte, or potential marrow donors

Prognostic Factors in AML

Favorable
young age	reactivity with CD2(T1)
FAB types M2, M3, M4	t(8;21) and t(15;17) abormality
inversion of chromosome 16
Unfavorable
older age	low labeling index/aneuoploidy
FAB type M7	trisomy 8
hyperleukocytosis	deletion of all or part of chromosomes 5 and/or 7
prior treatment	abormalities of chromosome 11 at band q23
prior heamtologic disorder
infection

• Although other cutoffs have been used, age greater than 60 is usually considered a poor prognostic factor because older patients generally don't tolerate therapy as well as younger patients. They also have a higher likelihood of having unfavorable prognostic factors such as special cytogenetic abnormalities.
• Types M2, M3, and M4 have the best prognoses, types M5 and M6 have variable prognoses, and type M7 has the worst prognosis.
• The presence of certain cell surface markers such as CD2 appears to be associated with a favorable prognosis.

DANIL HAMMOUDI.MD

SINOE MEDICAL ASSOCIATION