THE LEUKEMIAS

THE LEUKEMIAS
DEFINITION:
• The leukemias are a heterogenous group of neoplasms arising from the malignant transformation of hemopoietic (blood-forming) cells
• They primerly proliferate in the B.M & lymphoid tissues
• Where they interfere with normal hemopoiesis & immunity
• Ultimately they emigrate into the peripheral blood & infiltrate other tissues.
CLASSIFICATION:
• Leukemias are classified according to the cell types primarily involved into myeloid & lymphoid
• And as acute or chronic based upon the natural history & clinical course of the disease
• Acute leukemias have a rapid clinical course, resulting in death within a matter of months without effective treatment
• Whereas chronic leukemias have a more prolonged natural history
ETIOLOGY:
• The cause is unknown in most patients although both genetic & envirnmental factors may be important
• It occurs with an increased frequency in a variety of congenital disorders
• Ionizing radiation causes leukemias in experimental animals
• Chemicals such as benzene & other aromatic hydrocarbons associated with AML development.
• Leukemias induced by retroviruses (RNA viruses) have been studied in laboratory animals
• It wasn’t established untill recently as etiology for human leukemia
• A unique human retrovirus called human T-cell leukemia virus I (HTLV-I)
• Identified as causing adult T-cell leukemia (ATL)
• No virus has been causally associated with more common human acute & chronic leukemias
INCIDENCE & PREVALENCE:
• The incidence of all leukemias is approximately 13 per 100,000 people per year
• The acute leukemias comprise over half of the leukemias seen in clinical practice
• Also it is age related in acute & chronic
• ALL is the common form in children, with it’s highest incidence at 3-4 years falling off by 10 years
• After which it has a lower frequency with a secondary rise after 40 years old
• AML occurs in all age group
• It is the common form of acute leukemias in adults
• & the usual type to complicate myelodysplasia & other hematological diseases
• AML comprise only a minor fraction (10-15%) of the leukemias in childhood
THE ACUTE LEUKEMIAS:
PATHOPHYSIOLOGY:
• The leukemic cells in AML & ALL probably result from clonal proliferation
• This is by sucessive divisions from a single a normal stem cell or progenitor cell
• The mechanism of leukemogensis is poorly understood but involves a fundemental alteration of the DNA
• Conferring hereditable malignant transformation
• The blast cells fail to differentiate or mature normally but are capable of further divisions
• Their accumulation results in replacement of the normal hemopoietic precursors cells of the B.M
• This is by B.M myeloblasts or lymphoblasts
• Ultimately causes B.M failure
• The clinical condition of the patient can be correlated with the total number of leukemic cells in the body
• When their number approaches 10 12 the patient is usually gravely ill with severe B.M failure
• Peripheral blood involvement & organ infiltration (liver, spleen & lymphnodes) may not occur until leukemic cells comprises 60 % of marrow cell population
• The disease can be recognized morphologically only when marrow blasts exceed 5% of cell total
• Corresponding to a total cell count in excess of 10 8
• A collaborative group of French, American & British group of hematologists has divided AML into seven pathologic subtypes
• Basing upon the degree of differentiation & maturation of the predominant cells
• Towards granulocytes, monocytes, erythrocytes or megakarocytes
• The characteristics of each subtype is summerized in the next table
• There are only subtle differences in the clinical features of each subtype
• The acute promyelocytic one (M3) is frequently associated with DIC
• Induced by thromboplastic materials released by leukemic cells
FAB Classification of AML:
• M0: it is AML with no differentiation
• M1:with minimal differentiation
• M2:with more differentiation, Auer rods may be seen
• M3:promyelocytic leukemia
• M4:A. myelomonocytic leukemia
• M5:A. monocytic leukemia of two types (a) undifferntiated (b) differentiated
• M6:A. erythroleukemia
• M7:A. megakaryocytic leukemia
FAB Classification of ALL:
• Three morphologic subtypes:
1. L1:cells are small & homogeneous with a regular nuclear membrane & a small nucleolus
2. L2:are larger & have a lower nuclear-cytoplasmic ratio with pleomorphic size & shape & typically one or more prominent nucleoli
3. L3:is uncommon (<5% of cases) & contain large vesicular nuclei with basophilic vacuolated cytoplasm
CLINICAL FEATURES:
• Due to B.M failure
1. Pallor, lethargy & dysponea from?
2. Fever, malaise, features of mouth, throat, skin respiratory or other infections?
3. Spontaneous bleeding due to thrombocytopenia
4. Bleeing tendency due to DIC occurs in M3
• Due to organ infiltration:
1. Tender bones especially in children
2. Superfacial lymphadenopathy especially in ALL
3. Moderate splenomegaly, hepatomegaly especially in ALL
4. Gum hypertrophy & infeltration, skin involvement especially in M4 & M5
5. Lysosymes released by the blast cells may cause renal damage & hypokalemia (M5)
6. Meningeal syndrome particularly in ALL & more rarely AML especially M4 & M5
• Including headache, nausea & vomiting, blurring of vision & diplopia
7. Other occasional manifestations of organ infiltration include testicular swelling in ALL or signs of mediastinal compression in T-ALL
LAB FINDINGS:
• Hematology:
• A normocytic normochromic anemia
• The total white blood cells may be decreased (aleukemic or subleukemic leukemia), normal or increased ≤ 200X10 9/L
• Thrombocytopenia in most cases often extreme in AML
• T.B.F typically shows variable numbers of blast cells & may contain Auer rods (AML)
• Other abnormal cells may be present e.g promyelocytes, myelocytes, agranular neutrophils etc
• In M6 many erythroblasts may be found & in smaller numbers in other forms
• B.M examination:
 Displayes myeloid hyperplasia with marked proliferation of leukemic blast cells
 They amoumt over 50%, typically 70% of marrow cell total
 In ALL the marrow may be difficult to aspirate because of increased reticulin fibre
 In M7 the patient typically has an acute onset of pancytopenia with marrow fibrosis
• Special Investigations:
1. Differentiation of ALL from AML:
• in most cases, the clinical features & morphology on routine staining separate them
• In ALL the blasts show no differentiation unlike AML of some differentiation evidence
• Special tests are needed when the cells are undifferentiated to confirm diagnosis or subdivide cases of ALL or AML into subtypes
2. Cytochemistry :
• This may help to show granule development or monocytic differentiation in AML & help distinguish ALL subtypes
3. Immunological markers:
• These are used to distinguish AML from ALL & are particularly useful in subclassifying ALL
4. Chromosome analysis:
• Certain chromosome changes are typical of different subtypes of AML or ALL
• They are therefore useful in diagnosis & in monitoring for residual disease during therapy
• Chromosomal changes may carry prognostic significance e.g
• Ph+ ALL has a poor prognosis where as hyperdiploidy in ALL is a good prognostic feature
• Therefore can be useful in planning therapy
Hybrid Leukemia:
• In a minority of cases of acute leukemia, blasts show features of both AML & ALL on special testing
• These features may be on the same cell (biphenotypic)
• Or on separate populations (bilineal)
• Treatment is usually given on the basis of the dominant pattern

H.W
Write on the followings:
• immunological classification of acute leukemias
• Biochemical findings in acute leukemias
• Treatment of acute leukemia & its correlation with lab findings