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Acute Leukemias and their Diagnosis, Acute Myelocytic and Acute Lymphocytic Leukemia

Acute Leukemias and their Diagnosis, Acute Myelocytic and Acute Lymphocytic Leukemia
April 17, 2021HematologyLab Tests

Sample

  1. Blood in EDTA and fresh blood smear needed.
  2. Bone marrow aspirate and biopsy are required.

Definition of acute leukemia

  1. Leukemias are characterized by the uncontrolled (malignant) proliferation of the cells of the blood and bone marrow.
    1. In the case of a lymphocytic variety, there is the involvement of the lymph nodes.  OR
  2. This is a malignant neoplasm of hematopoietic cells particularly stem cells.  OR
  3. There is diffuse infiltration of the bone marrow by these neoplastic cells. OR
  4. Leukemias are the malignant disease of the hemopoietic tissue, characterized by the replacement of normal bone marrow elements with abnormal neoplastic blood cells.
  5. These cells enter the blood and may infiltrate the liver, spleen, lymph nodes, and other organs.
    Acute leukemia development from the stem cells and clinical presentations

    Acute leukemia development from the stem cells and clinical presentations

Classification of Acute Leukemias

  1. On the morphology of the cells, these are divided into:
    1. Acute lymphocytic leukemia (ALL), involving the lymphocytes and their precursors.
    2. Acute myelocytic leukemia (AML), involving the granulocytes and their precursors.
    3. Acute monocytic leukemia, involving the monocytes and their precursors.
    4. Acute plasmacytic leukemia, involving the plasma cells and their precursors.
    5. Acute erythroblastic leukemia, involving the red blood cells precursors.
  2. Acute leukemia develops from the stem cells and developed into myelocytic and lymphocytic varieties.
    Development of Acute leukemias

    Development of Acute leukemias

Pathophysiology

  1. The malignant transformation is at the level of pluripotential cells (stem cells) and these cells change into committed stem cells, and they basically called stem cell disorder.
  2. There is abnormal proliferation, monoclonal expansion, and decreased apoptosis of these cells leads to the replacement of normal bone marrow cells by these malignant cells or immature cells.

Clinical features of acute leukemias are:

Acute Leukemias Criteria:

  1. Acute leukemias are characterized by abnormal differentiation and proliferation of malignantly transformed hematopoietic blast cells.
  2. These cells proliferate in the bone marrow and lead to the suppression of the normal cells.
  3. These have little or no maturation and may see mainly blast cells.
  4. Acute Leukemias are diagnosed on the percentage of blast cells in the bone marrow.
  5. 30% or more blast cells are needed to classify the disorder as acute leukemia.
  6. These leukemias are associated with varying degrees of anemia, neutropenia, thrombocytopenia, and or infiltration of the tissues.
    1. The most common site of infiltration is lymph nodes, liver, spleen, CNS, and skin.

Epidemiology of acute leukemias:

  1. ALL and AML can occur at any age. But the incidence increases with the increasing age.
  2. ALL predominates in the children, while AML accounts for the majority of the cases in adults.
  3. AML’s median age is around 60 years.
  4. The peak age for ALL is between 3 to 5 years. These are morphologically different than adult cases.
  5. Acute leukemias more common in whites than blacks.
  6. Acute leukemias more common in the jews than the non-jews.
  7. Acute leukemias are more common in men than in women.

Etiological factors for acute leukemias (Risk factors):

  1. The cause of acute leukemias is unknown, this may be hereditary or environmental factors.
    1. The pathogenesis is very complex and this may involve interaction between the host susceptibility, and chromosomal damage secondary to physical or chemicals agents.
  2. Chromosomal abnormality:
    1. Deletion:
      1. 5q –  = Myelodysplasia, preleukemia.
      2. Monosomy 7.
    2. Inversion:
      1. inv 16 = AML.
    3. Translocation:
      1. t18:14 = Burkitt’s lymphoma.
      2. t8:21 = AML.
      3. t4:11 = ALL.
      4. t9:22 = CML
  3. Oncogenes:
    1. C-abl, C-sis = CML.
    2. C-myc = Burkitt’s lymphoma (L3).
  4. Viruses:
    1. There are viruses known to give rise to leukemia in nonhuman species.
    2. The human role of viruses is studied for a long time but no conclusive data is available.
    3. Epstein-Barr virus is seen in the majority of Burkitt’s lymphoma.
    4. The Human T-leukemia virus  (HTLV-1) is associated with acute leukemia.
  5. Inherited factors:
    1. The following examples favor the role of genetic abnormalities:
      1. Increased incidence of acute leukemia in families.
      2. Increased incidence of acute leukemia in the monozygotic twins.
        1. If one twin has leukemia, the other is also at risk for leukemia, often before 8 years of age.
        2. Leukemia starts in the next twin within a year of the first diagnosis.
    2. Increased incidence of acute leukemias in members of a certain family with high susceptibility, the high increased frequency leukemia in monozygotic twins, an association of acute leukemias genetic disorders, all these factors have established that hereditary abnormalities play role in the development of acute leukemia.
    3. There is an increased incidence of AML and ALL in Down’s syndrome where there is trisomy 21.
      1. 5 to 10% of childhood AML occurs in Down’s syndrome.
    4. There is an increased incidence of Fanconi’s syndrome and Bloom’s syndrome.
      1. Both conditions are hereditary and there is an increased chromosomal breakage.
    5. Ataxia-telangiectasia and congenital agammaglobulinemia have chromosomal abnormalities that are associated with acute leukemia.
  6. Acquired factors:
    1. Drugs and Chemicals:
      1. Alkylating drugs like nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, and procarbazine.
        1. Benzene compounds and pesticides.
      2. Exposure to melphalan or nitrogen mustard is associated with acute AML after 5 to 7 years of exposure.
        1. The patient will have pancytopenia, myelodysplasia, and cytogenetic abnormalities (there is a total loss or partial loss of chromosomes 5 and 7).
        2. Hodgkin’s lymphoma, Multiple myeloma, and ovarian cancer treatment complication of AML is a well-known example.
        3. Benzene complication of acute leukemia is well-known.
    2. Radiation: The leukemogenic potential of ionizing radiation is recognized for a long time.
      1. Mostly myeloid leukemia takes origin the radiation.
      2. Fetal exposure to radiation increases the risk of childhood leukemia.
Type of cells % of the cases FAB subtype
Pre B- cells ALL 75 L1 and L2
B-cell ALL 5 L3
T – cell ALL 20 LI and L2

Acute Leukemias signs and symptoms

  1. Appears suddenly.
  2. The patient may have weakness and fatigue.
  3. The patient may have a low-grade fever.
  4. There may be bruising and mild bleeding from the gums.
  5. There is bone pain due to the expansion of the marrow.

Clinical features of acute leukemias are due to:

Pathology  Signs and symptoms
Bone marrow failure leads to:
Anemia This will cause:

  1. Fatigue
  2. Malaise
  3. Pallor
Thrombocytopenia This will leads to:

  1. Bleeding
  2. Bruising
Leucopenia This will leads to:

  1. Frequent infections
  2. Fever
Metastasis or infiltration of the other organs:
Bone marrow involvement There is bone or joint pain
Involvement of spleen There is splenomegaly
Infiltration of the liver There is hepatomegaly
Infiltration of the lymph nodes There is lymphadenopathy
Involvement of gum and mouth
  1. There is gingival hypertrophy
  2. There are oral ulcers
Involvement of the central nervous system (CNS) There are neurologic symptoms

Diagnosis of Acute Leukemia

  1. Clinical features:
  2. These are more common in the younger age group.
    1. These are more frequent in children.
    2. Mostly seen before the age of 20 years.
  3. Onset is an abrupt and fatal outcome.
    1. There is a fever.
  4. There is a rapid development of anemia.
    1. There is normochromic and normocytic anemia.
    2. May see nucleated RBCs.
  5. There is thrombocytopenia.
    1. May see petechiae and purpura in the skin and mucous membranes.
  6. Leukocyte count is variable.
    1. Mostly leucocyte count is less than 100,000/cmm.
  7. Diagnosis depends upon the microscopic examination of the blood and bone marrow.
  8. Immunohistochemical staining.
  9. Immunophenotyping by the flow cytometry to distinguish T-cell, B-cell, and non-T, non-B cells type of ALL. This is very important because of the response of all these three types of leukemias.
  10. Cytogenetic studies can also be advised.
    1. Chromosomal abnormalities are seen in >50% of the cases

Difference between acute and chronic leukemias:

Clinical features  Acute leukemia Chronic leukemia
Age incidence All ages Mainly seen in adults
The onset of the disease There is sudden onset There is an insidious onset
The course of the disease <6 months It usually 2 to 6 years
Type of the leukemic cells Mainly immature cells (blast cells) Mainly mature cells
The severity of the anemia This is mild to severe This is usually mild
Platelets status Mild to severe thrombocytopenia Mild thrombocytopenia
WBCs count It is variable It is usually increased
Involvement of the organs This is mild This is quite prominent

Treatment Goals

  1. The main aim of the therapy is to the restorative bone marrow function and to normality.
  2. Complete remission when the patient had full recovery of the peripheral blood smear and bone marrow showing <5% of the blast cells.
  3. Induction therapy aims to reduce the total body leukemia cell population roughly from 1012 cells to below <109.
  4. The complication of the chemotherapy:
    1. Cytotoxic drugs lead to:
      1. Tumor lysis syndrome and urate nephropathy.
        1. Hyperuricemia responds rapidly to rasburicase.
        2. Allopurinol, I/V therapy, and alkalinization of the urine reduce the chances of uric acid precipitation in the renal tubules.
      2. Electrolytes imbalance like hyperkalemia, hypocalcemia, and hyperphosphatemia.
      3. There may be a gastrointestinal injury, diarrhea, and mucositis.
      4. There may be thrombocytopenia, bleeding, and neutropenic infection.
      5. Blood products are given to maintain the platelets count >10,000 µL in non-bleeding patients, and hematocrit to keep >25%.
      6. Antibiotics are given if the body temperature is >38.5 °C.
      7. In neutropenic patients when TLC is <500 /µL, antifungal therapy is added for these febrile patients.

Acute Myeloid Leukemia (AML)

  1. Pathogenesis:
    1. There are primary AML that appear de novo.
    2. Secondary AML which develops from:
      1. The myelodysplasia.
      2. Other hematological diseases such as myeloproliferative disorders.
      3. Or following previous treatment with chemotherapy.
  2. Age: This is seen during the first month of life and then in the later age group.
    1. 10 to 15% of cases found in the children.
    2. If there is exposure to high-energy radiation in early childhood life has an increased risk for developing T-cell acute lymphoblastic leukemia.
  3. Sex: More common in males than women. Male: female ratio is 3:2.
  4. Signs and symptoms:
    1. Mostly these patients present with a varying degree of bone marrow failure.
    2. So clinical symptoms and signs are due to anemia, leukopenia, thrombocytopenia, and infections.
      1. About 1/3 of the patient have bruises and hemorrhages.
      2. About 1/4 of the patients have severe infections involving the lungs, soft tissue, or skin.
      3. Splenomegaly and hepatomegaly are not common and seen in<25% of the cases.
      4. Lymphadenopathy is even less common.
      5. Gingival hypertrophy or skin infiltration by the tumor occurs in 50% of the patients with monocytic leukemia.
      6. Acute promyelocytic leukemias are more commonly seen with severe bleeding from the DIC.
    3. Fever and fatigue are present in most of the patients.
    4. Acute promyelocytic leukemia (M3) causes disseminated intravascular coagulopathy (DIC) and bleeding.
    5. Acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) cause gum hypertrophy.
    6. There may be tumor infiltrate of AML called granulocytic sarcoma (Chloroma), skin, and the bone particularly the sternum, ribs, and orbit are common sites.  Myeloid sarcomas may involve any organs.
    7. These patients may have respiratory distress due to leukostasis within the pulmonary vasculature.
    8. There may be retinal hemorrhage due to thrombocytopenia.

Classification:

French-American-British (FAB) Classification of Acute Myelocytic Leukemia:

FAB has 85% concordance. This is based on morphology and cytochemistry. Immunophenotyping and cytogenetics give additional information for the treatment.
WHO criteria for the AML is ≥20% blast cells.

FAB type Characteristic features Frequency
M0 Acute myeloblastic leukemia with minimal differentiation.

  1. Blast cells lake cytologic and cytochemical markers of the myeloid series cell. But express myeloid series lineage antigens.
  2. 2 to 3% of AML.
  3. Bone marrow contains ≥30% of the blast cells, that don’t fulfill FAB criteria.
  4. Sudan black and myeloperoxidase stains are negative. express CD13 and CD33 antigen-positive on the surface.
  5. These are not included in the current FAB classification.
  6. Immunologic markers or E/M needed for the diagnosis.
 2 to 3%
M1 Acute myeloblastic leukemia without differentiation.

  1. Its incidence is ≤20% of the AML cases.
  2. Undifferentiated myeloblastic cells. >90% of the cells are blast cells, predominantly type 1.
  3. <10% of the cells are granulocytic series.
  4. No cytoplasmic granules,  may see few.
  5. Only 3% of the cells are myeloperoxidase positive.
  6. Auer rods are common (another reference says few Auer rods).
    AML, M1

    AML, M1

 20%
M2 Also called AML with maturation.

  1. Incidence is 25% to 30% of the AML patients.
  2. Patients are of younger age, with a mean age of 28 years.
  3. There is splenomegaly in 28% of the cases.
  4. Chloromas, especially of the face is seen in 20% of the patient.
  5. Differentiated myeloblastic (30 to 89%) cells and sparse granules and abundant cytoplasm.
  6. Myelocytes and promyelocytes are predominant.
    1. >30% blast cells
    2. Myeloblast with Auer rods is seen in 60% to 70% of the cells.
  7. Monocytic cells are <20%.
  8. Eosinophils precursors are increased and contain Auer rods.
  9. Some of the cells are myeloperoxidase or Sudan black positive
  10. Cytogenetics show t(8;21)and (q22;22q).
  11. Frequent loss of sex chromosomes.
  12. May be seen in down syndrome (trisomy 21).
  13. Prognosis:  75% to 85%  of the cases go into complete remission after the chemotherapy.
  14. Median survival is 9.5 months duration on average.
    AML, M2

    AML, M2

 25 to 30%
M3 Acute Promyelocytic Leukemia.

  1. These are 5% to 10% of the AMLcases.
  2. The median age is 31 years.
  3. These patients present with bleeding episodes, and ≤47% die of fatal hemorrhage.
  4. DIC is seen in ≤80% of the cases.
  5. Blast cells are <30% in most cases.
    1. Blast cells contain prominent granules, nuclei are bilobed, or kidney-shaped.
  6. Granules are typical of promyelocytic morphology, these are azurophilic.
  7. Auer rods are many. These are strongly myeloperoxidase positive.
  8. Cytogenetics show t(15;17), t(11;17), and (q22;q11-12) are diagnostic for M3.
  9. M3v variant:
    1. These are micro granular types.
    2. 20% of the AML cases are this type.
    3. WBCs count is high 50,000 to 200,000 µL with small, and difficult to see azurophilic granules.
      AML, M3

      AML, M3

5 to 10%

(8 to 15%)
M4 Acute Myeloid Monoblastic Leukemia (Acute myelomonocytic leukemia).

  1. 20% to 25% of the AML cases are this type.
  2. The mixed population of myeloblastic (>30%), and monocytic (>20%) morphology.
    1. ≥30% of the cells are myelomonocytic blast cells.
      1. 2% to 8% are myelocytic origin.
      2. 20% to 80% are monocytic origin.
    2. The peripheral blood smear shows typical myelomonocytic blast cells.
  3. Auer rods may be seen.
  4. Nonspecific esterase and chloroacetate stains are often positive.
  5. Karyotype shows inversion or deletion of chromosome 16 [inv(16)(p13;q22)].
  6. Cytochemistry is needed for the diagnosis of AML, M4.
    1. There is weak staining of nonspecific esterase.
  7. Prognosis in 70% to 90% of cases is complete remission with a prolonged median survival of >18 months.
    1. >1/3 cases come with relapse of CNS involvement.
      AML, M4

      AML, M4

20 to 30%

(20 to 25%)
M5 Acute Monoblastic Leukemia.

  1. These are 10% of the AML patients.
  2. It involves mostly children and young adults.
  3. Pure monoblastic cells. Monoblast and promonocytes predominate constitute >80%.
  4. These leukemic cells may infiltrate skin or the gums, and CNS.
  5. DIC is frequent in these cases.
  6. Serum lysozyme is often raised.
  7. There are poor survival and shorter remission.
  8. >30% cells are blast cells and >80% are monocytoid differentiation.
  9. Cytogenetics show t(9;11), (p22;q23), and t(11;q23).
  10. M-5a variant:
    1. This is called monoblastic leukemia.
    2. 4% are poorly differentiated  AML.
    3. >80% of the cells are monoblasts.
  11. M-5b variant:
    1. 6% of the AML cases.
    2. <80% of the cells are monoblasts.
    3. A karyotype is t(9;110)(p22;q23)
      AML, M5

      AML, M5

 10%
M6 Acute Erythroleukemia.

  1. 4% to 5% of the AML patients.
  2. Predominantly immature erythroblast ≥50%, and can see multinucleated megaloblastoid erythroblast.
    1. There are megaloblasts, ringed sideroblast, and Howell-Jolly bodies are common.
    2. Nucleated RBCs in the peripheral blood are common.
    3. Anemia is also common.
  3. Erythroblast cells are strongly PAS-positive.
  4. Myeloblasts are 30% or more.
    1. If <30% then the diagnosis is a myelodysplastic syndrome.
      AML, M6

      AML, M6

 5%
M7 Acute Megakaryoblastic leukemia.

  1. 1% to 2% of the AML cases.
  2. These cases are common in Down syndrome between the age of infancy and 3 years.
  3. Megakaryocytic  Cells small and large in size with shaggy borders that may show some budding.
    1. Megakaryoblasts are ≥30% of all the cells.
    2. Blast cells are highly polymorphic and often labeled as undifferentiated cells.
    3. Mature megakaryocytes are also present.
  4. There is a high N/C ratio.
  5. There is myelofibrosis almost in all patients.
    1. 20% to 40% cases are presented with acute myelofibrosis, making blast cells counting difficult.
  6. Platelet peroxidase and platelets antibodies are often positive.
  7. Cytogenetics show t(1;22), and (p13;q13).
    AML, M7

    AML, M7

1 to 2%

(1%)

Summary of the FAB classification of acute myelocytic leukemia:

Abbreviation of FAB Differentiating features of AML cells Type of leukemia
M1 There are undifferentiated myeloblastic calls AML-M1 (AML I= Acute myeloblastic leukemia)
M2 There are early signs of myeloblastic cells differentiation AML-M2 (AML II =Acute myeloblastic leukemia)
M3
  1. There are promyelocytes with abundant granules.
  2. There are abundant Auer rods
 AML-M3 (AML III =Acute promyelocytic leukemia)
M3 (var)
  1. There are fewer granules
  2. There are bi- or multilobed nuclei
  3. There are few Auer rods
 AML-M3 (var) (AML III (var) = Variant of Acute promyelocytic leukemia)
M4
  1. There are immature granulocytes and monocytes
  2. Myeloblastic cells are >30%
 AML-M4  (AMML=Acute myelomonocytic leukemia)
M4-Eo There are abnormal eosinophils AML-M4 (AMML-Eo=Acute myelomonocytic leukemia with abnormal eosinophils)
M5 There are differentiated and undifferentiated monoblastic cells AML-M5 (AMoL= Acute monoblastic-monocytic leukemia)
M6
  1. There are abnormal erythropoietic cells
  2. Myeloblastic cells are also seen
 AML-M6 (AEL= Acute erythroleukemia)
M7 There are megakaryoblastic cells AML-M7 (AMegL= Acute megakaryoblastic leukemia)
  1. Lab. findings : 
    1. WBC count is variable. 25% of the patient has >50,000/cmm, 25% has <5000/cmm and 5 to 10% has count between 5000 to 10,000/cmm.
      1. A count>100,000/cmm is reported in <10% of the patients but these patients have severe CNS or respiratory diseases due to leukostasis.
      2. In these patients, leukapheresis and chemotherapy may be life-saving.
    2. WBC morphology. These are morphologically abnormal and immature cells.
      1. 20% or more of the blast cells in the bone marrow as diagnostic of AML.
        1. Ther blast cells of AML are larger than lymphoblast cells and greater heterogeneity in size and shape.
        2. AML blast cells mostly abundant cytoplasm and often contain cytoplasmic granules.
        3. About 10% of the AML cases show Auer rods and azurophilic granules with Wright’s stain.
      2. The peripheral blood smear may show blast cells in 85 to 90% of the cases.
      3. FAB divide AML into:
        1. M1, M2, and M3 with granulocytic differentiation.
        2. M4, M5 with at least 20% monocytoid appearance.
        3. M6 with a high proportion of erythroblasts.
        4. M7 with predominantly megakaryoblasts.
        5. M0 with minimal myeloid differentiation. This needs immunohistochemical stains for the diagnosis. These cases have myeloid antigens on their surface and myeloperoxidase activity is negative.
    3. Uric acid in 50% of the cases is raised which indicates increased cell turnover.
    4. Lactate dehydrogenase (LDH) about 50% shows a raised level. This is not as common as in ALL.
    5. Bone marrow shows >20% blast cells. Promyelocytes are numerous particularly in M3.
      1. Auer rods can be seen in the cytoplasm.
      2. Cytochemical stains, peroxidase reaction, and Sudan black are positive.
    6. Nucleated RBCs may be seen.
    7. Platelet count may be low and may see count between 30,000 to 100,000/cmm. In some cases may be <20,000/cmm.
    8. Coagulation abnormalities are also seen. PT, PTT, and Thrombin time are prolonged.
  2. Treatment: There is a supportive and specific treatment for AML.
    1. Stem cell transplantation, autologous transplantation may be done. But because of the toxicity overall no benefit.
    2. The treatment of patients over 70 years of age of AML is poor because of primary disease resistance and poor tolerability of intensive treatment.
      1. Death in old people is usually from hemorrhage, infections, and failure of the heart, kidneys, or other organs as compared to the younger patients.
  3. Prognosis:
    1. 50% of children and young adults may have a long-term cure.
    2. Recently with the newer advanced chemotherapy, the prognosis in the 60 to 70 years of age is better.
    3. Cytogenetics abnormalities and initial response to the treatment are the major predictors for the prognosis.
    4. AML overall complete remission is 60 to 70% and disease-free survival is 20 to 40%.
      1. <60 years complete remission is 70 to 80% and disease-free survival is 40%.
      2. >60 years complete remission is 45 to 55% and disease-free survival is 5 to 10%.
      3. AML and prognostic factors:
        Clinical parameters Good prognosis Poor prognosis
        Age <60 years >60 years
        Onset of AML Primary Secondary
        BM response to remission induction <5% blast cells after one course of chemotherapy 20% blast cells after the first course of chemotherapy
        Cytogenetics t(15;17), t(8;21), inv(16), NPM mutation t(6;9), 11q23, abn(3q), deletion of chromosome 5 or 7

 Acute Lymphoblastic Leukemia (ALL)

  1. Age:  ALL constitute 20% of adult leukemia and these are more common in children.
    1. In adults 80% of the ALL are B-cells and 20% are T-lymphocytes origin.
    2. This is most common in childhood. Mostly occur before the age of 4 years. The peak is between 2 to 10 years, it is also called childhood leukemia.
      1. ALL comprises >80% of childhood leukemia.
      2. 90% have chromosomal abnormalities.
      3. Down syndrome has a 15x times higher incidence of ALL.
    3. These are rare after the age of 30 years.
    4. These are most common in children and young adults.
    5. The second peak may be seen in the middle and old age groups.
    6. L3 leukemia is most common in developing countries and may be associated with the infection by the Epstein-Barr virus in the younger age group.
    7. Children with trisomy 21 (Down’s syndrome) have an increased risk for childhood acute lymphocytic and also acute myelocytic leukemias.
    8. An increased incidence is seen in immunodeficiency diseases like ataxia-telangiectasia, osteogenesis imperfecta, siblings of ALL, and Poland syndrome.
  2. Signs and symptoms:
    1. S/S of acute AML and ALL are similar, except the onset of ALL is strikingly acute.
    2. Onset is sudden. There is no preleukemic stage.
      1. Symptoms are present only for a few weeks before the diagnosis.
    3. There are fatigue and fever. There is malaise, lethargy, and weight loss.
    4. There may be bleeding and infections.
    5. There is an enlargement of lymph nodes, spleen, and liver is more common than the AML affecting 50% of the adults.
    6. There may be involvement of the central nervous system (CNS) in 5 to 10% of the cases.
      1. This shows leukemic meningitis.
      2. Cranial nerve palsy more common in the 6th and 7th nerves.
      3. There are headaches and papilledema due to meningeal involvement and the obstruction of the outflow of CSF.
      4. CSF shows increased protein and leukemic cells.
    7. Bone pain is due to the infiltration of the leukemic cells.
    8. Retinal hemorrhage is due to thrombocytopenia.
    9. Chest X-ray shows a thymic mass in 10 to 15% of the adults.
  3. Classification:
    1. Classification of ALL is based on cytological features like:
      1. Cell size.
      2. Nuclear chromatin pattern.
      3. Nuclear shape.
      4. Presence of nucleoli.
      5. Amount of basophilia in the cytoplasm.
        1. 80% of the ALL are B-lymphocytes origin.
        2. 15 to 20% of cases arise from T-lymphocytes. These cells will express CD2, CD5, and CD7.
          1. T- L ALL are lacking CD19 and CD20.
    2. L1 – ALL account for >80% of the cases in children and consists of predominantly small, up to twice the size of small lymphocytes.
    3. L2 – ALL are the majority of adult leukemia. The cells are larger than in the L1 and often heterogeneous in size.
    4. L3 – ALL is the least common form of approximately 3 to 4% of the children and the adults. The cells are morphologically identical to the cells in Burkitt’s lymphoma.
    5. FAB is no longer used.

FAB (French-American-British) classification of Acute Lymphocytic Leukemia:

L1
  1. Lymphoblasts with uniform, round nuclei, and scant cytoplasm.
  2. Nucleoli are not prominent.
ALL- L l

ALL- L l
L2
  1. More variable lymphoblast and cytoplasm are abundant.
  2. Nucleoli are large and may see one or more nucleoli.
ALL- L2

ALL- L2
L3
  1. Lymphoblasts with fine nuclear chromatin and blue to deep blue cytoplasm that contains vacuoles.
  2. Lymphoblast is large and has prominent nucleoli and these are one or more than one.
ALL-L3

ALL-L3

Cytochemical classification of Acute lymphoblastic leukemia (ALL):

Type of leukemia Periodic acid-Schiff reaction (PAS) Acid phosphatase reaction (AP) Terminal deoxynucleotidyl transferase reaction (TdT)
c-ALL (common ALL) >70% coarse, lumpy, granular (++) Negative (rare cases +) Positive (+)
T-ALL (L1 and L2) <40%, granular (+) >80%focal (++) Positive (+)
B-ALL (L3) Negative to positive (- to +) Granular (+) Negative (-)
B-ALL (AUL- lymphocytic origin) Negative to positive(- to +) Negative to positive (- to +) Positive (+)
  1. Lab. Findings:
    1. Lab diagnosis depends upon:
      1. Morphology.
      2. Cytochemistry.
      3. Immunophenotyping.
      4. Genetic analysis.
    2. WBC count is variable from very high to low count.
    3. There are anemia and thrombocytopenia.
  2. Bone marrow: Very few leucocytes are seen.
    1. Difficult to find normal WBCs or RBCs in the bone marrow.
    2. Characteristically there are blast cells. >50% are lymphoblastic cells.
    3. Auer rods are absent.
  3. Serum LDH, uric acid, and ESR are often raised.
  4. Flow cytometry studies (differentiation of the antigens over the surface of these abnormal cells) provide rapid diagnosis.
    1. 80% of the ALL arises from the B-lymphocytes and will show CD molecules of CD19, CD20, or both.
    2. Few cases of the ALL may show CALA (common ALL antigen) which is CD10.
    3. Roughly 20% of the CD10-positive cases may show cµ and are called pre-B – ALL.
  5. Special stains:
      1. Sudan’s black and peroxidase reactions must be negative to support the diagnosis of ALL.
      2. PAS stain shows clumpy positivity by glycogen in all ALL except the L3 which is negative..
      3. Cloroectate esterase and lysozyme stains negative in all ALL.
      4. α-naphthyl acetate esterase may be positive in T-lymphoblast.
      5. All cases of ALL contain TdT (terminal deoxynucleotidyl transferase) enzyme and this fairly reliable marker of the ALL.
      6. ALL – L3 often stains with oil red O because of the presence of neutral lipids present in the vacuoles.
    2. Morphology of the cells:
      L1 Small uniform blast cells
      L2 Larger and more variable size of the cells
      L3

      1. Uniform cells with basophilic and sometimes vacuolated cytoplasm, typical of Burkitt’s lymphoma.

      2. Philadelphia chromosomes-positive in acute lymphoblastic leukemia and t(8;14) found.
  6. Treatment:
    1. The aim is to restore the normal function of the bone marrow by multiple chemotherapy drugs.
    2. Typically four drugs e.g. vincristine, prednisone, daunorubicin, L-asparaginase, and cyclophosphamide are used for induction and remission.
    3. 80 to 90% of the adult enters complete remission.
    4. around 30 to 50% will be alive free of disease for 3 years.
  7. Prognosis:
    1. Patients with a count >30,000/cmm have a shorter duration of remission than patients with a lower count.
    2. Older age >60 years is not a good favorable factor.
    3. Another factor that matters the prognosis are:
      1. Circulating blast cells %.
      2. The degree of bone marrow involvement.
      3. The presence of splenomegaly, hepatomegaly, and lymphadenopathy.
      4. LDH level.
      5. Involvement of the CNS at the time of diagnosis.
      6. The time needed to get the remission for 4 to 6 weeks.
      7. Ph1chromosome is present in ≤25% of adults and 3% in children. Its positivity shows poor prognostic signs.
    4. ALL overall 80 to 90% have complete remission and disease-free survival is 30 to 40%.
      1. T-ALL 90 to 95% have complete remission and disease-free survival is 60 to 65%.
      2. Precursor B-Cell ALL has complete remission of 75 to 85% and disease-free survival is 30 to 40%.
      3. ≥60 years complete remission of 75 to 80% and disease-free survival is 10 to 25%.
    5. Poor prognostic signs are:
      1. Platelets count <50,000/cmm.
      2. WBCs count >100,000/cmm.
      3. Pre-B phenotype.
      4. Cytogenetic abnormalities.
      5. CD10 seronegative type.

Difference between Acute Myelocytic Leukemia and Acute Lymphocytic Leukemia

Characteristic Features                    Acute Myelocytic Leukemia      Acute Lymphocytic Leukemia
Origin of the cells Myeloid series cells Lymphoid  series cells
Features of Blast cells Large in size, Small in size
Cytoplasm is moderate Cytoplasm is scanty
Chromatin is fine and lacy Chromatin is dense
Nucleoli are prominent and >2 Nucleoli are indistinct and <2
Auer rods Present Absent
Sudan black and peroxidase Positive Negative
Bone marrow A mixed population of myeloid cells and blast cells Mainly blast cells and very few  WBCs or RBCs
Leukocyte Alkaline phosphatase (ALP) Positive  (differentiate CML from the leukemoid reaction. Negative
Periodic Acid-Schiff (PAS) Positive in Erythroblast in M6 leukemia

Positive (block patterns) in L1 and L2

Negative in L3

Prognosis of the ALLand AML:

Type of leukemia Complete remission Disease-free survival
ALL
ALL (overall types) 80 to 90% 30 to 40%
Precursor B cell ALL 75 to 85% 30 to 40%
Ph1+  ALL 70 to75% 0 to 10%
Burkitt’s lymphoma 75% 70%
≥60 years 75 to80% 10 to 25%
AML
AML  (overall types)
 60 to 70% 20 to40%
Acute promyelocytic leukemia
 90% 70 to 75%
<60 years
 70 to 80% 40%
≥60 years 45 to 55% 5 to 10%

Test value for the layman:

  1. A blood examination is advised if the patient has a high TLC.
  2. If the patient has anemia.
  3. If the patient has enlarged lymph nodes.
  4. In the case of patients has a fever and weakness.
Possible References Used
Go Back to Hematology

Comments

Mohamed Reply
March 17, 2020

Thanks

Dr. Riaz Reply
March 17, 2020

Thanks for your comment

Taieb Agourram Reply
May 27, 2020

very informative and concise

Dr. Riaz Reply
June 6, 2020

Thanks for the comments.

Bob Quincel Reply
September 2, 2020

Pharm line is going down

TUYEN Reply
September 14, 2020

THANK YOU SO MUCH DR. RIAZ
I am in medical laboratory technician school now. Your website is a great source to learn

Dr. Riaz Reply
September 15, 2020

Thanks.

krishnakumar subramanian Reply
January 15, 2021

Thanks a lot sir

Abdullah Sarwari Reply
April 15, 2021

thanks from your information your website is really nice and

Dr. Riaz Reply
April 15, 2021

Thanks.

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