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Lesson 10-2
Classification of Leukemias


Most malignancies of the hematopoietic system are acquired genetic diseases, meaning that most patients are not born with the illness, but acquire sometime later in life. Most WBC malignancies or disorders are not localized but rather are systemic at the initiation of the malignant process. A single leukemia cell arising the bone marrow can obtain passage into the bloodstream and travel to any and all locations of the body, so most treatments given for curative intent of leukocyte neoplasms are not localized but must by nature be systemic-type treatment. The duration of the untreated disease is categorized as either acute or chronic.


  • Sudden onset, symptoms of short duration.
  • Total WBC count usually elevated, although some patients may have normal to decreased counts.
  • Anemia and thrombocytopenia usually present.
  • Prognosis of untreated disease - several weeks to several months.
NOTE: Median survival time for untreated acute leukemia is three months. Seventy percent of adults and 90 percent of children have at least one remission


  • Symptoms of long duration.
  • Total WBC count ranges from extremely elevated to lower than normal.
  • Anemia is not usually present until late in the disease; platelet counts usually normal.
  • Prognosis of untreated chronic forms - months to years.
  • Type of cells involved:
    • Acute leukemia. Predominance of immature cells (blast and “pro” stage).
    • Chronic leukemia. Predominance of mature cells.


Acute nonlymphoblastic leukemias (ANLL). General characteristics:

  • Mutant stem cells give rise to a monoclonal population of myeloid cells - impaired ability to differentiate beyond early forms of cells.
  • Blasts and other early forms replace normal cells in bone marrow - increased M:E ratio.
  • Symptoms: fever, malaise, fatigue, bleeding problems, and may include organ involvement.


M0 - Acute Myeloblastic Leukemia with Minimal Differentiation.

  • Predominant cells - blasts with no granulocytic maturation.
  • Myeloid antigens present on blasts, lymphocyte associated antigens absent.
  • Classification of M0 cannot be made solely on WBC morphological characteristics – cytochemical staining is required.

 M1 - Acute Myeloblastic Leukemia without Maturation.

  • Predominant cells - poorly differentiated myeloblasts without granulation (90% or more of nonerythroid cells).
  • Fine nuclear chromatin and one or more distinct nucleoli.
  • Moderate amount of cytoplasm.
  • Auer rods are rare.
  • Leukocytosis in more than 1/3 of patients, with total WBC > 100 X 109/L.

M2 - Acute Myeloblastic Leukemia with Maturation.

  • Predominant cells - myeloblasts (30 to 89 percent of nonerythroid cells).
  • Round or oval nuclei with one or more prominent nucleoli and fine reticular chromatin.
  • Basophilic cytoplasm with azurophilic granules.
  • Auer rods may be present.
  • Promyelocytes, myelocytes, metamyelocytes, and mature granulocytes present.
  • Leukocytosis common.

M3 - Acute Promyelocytic Leukemia.

  • Predominant cells - promyelocytes (greater than 30 percent).
  • Immature nucleus, bi-lobed or kidney-bean shaped.
  • Large cytoplasmic granules that may obscure nucleus.
  • Auer rods may be present in multiples or in bundles.
  • Disseminated intravascular coagulation (DIC) may occur.
  • Leukopenia to leukocytosis, leukopenia frequently seen.

M4 - Acute Myelomonocytic Leukemia.

  • Predominant cells - myeloblasts and monocytes (30 percent or more).
  • Leukopenia to leukocytosis with WBC count rarely exceeding 100 X 109/L.
  • Monocytic cells must account for 20 to 80 percent of the total WBCs in the bone marrow.

M5 - Acute Monocytic Leukemia.

  • Predominant cells - 80 percent monoblasts, promonocytes, and monocytes.
  • Less than 20 percent granulocyte precursor cells. (3) WBC count: 15-100 X 109/L.
  • Forms:
    • M5a. Poorly differentiated - large monoblasts with lacy, delicate chromatin and 3 to 5 nucleoli (80 percent or more of monocytic cells are monoblasts).
    • M5b. Differentiated form - high proportion of mature monocytes present in peripheral blood (less than 80 percent of all monocytic cells are monoblasts).

M6 - Erythroleukemia (Di Guglielmo's Syndrome).

  • Predominant cells - myeloblasts, immature granulocytic cells, immature RBCs including normoblasts.
  • WBC count - slightly decreased to moderately elevated.
  • Abnormal proliferation of erythroid and myeloid precursor cells.
  • RBC morphology - oval macrocytes, schistocytes, or mixed populations of hypochromic and normochromic red cells.
  • Bone marrow - decreased M:E ratio, 50 percent or more nucleated bone marrow cells are erythroblasts, 30 percent or more nucleated bone marrow cells are myeloblasts; see erythroblasts with bizarre morphology including megaloblastic changes, may see ringed sideroblasts with iron stain.
  • Erythroid cells exhibit various degrees of bizarre morphology (called dyserythropoietic changes) -- multi-lobed nuclei, multiple nuclei, nuclear fragments, gigantism, vacuolization, and megaloblastoid features.
  • Frequently progresses to M1, M2, or M4 leukemia.

M7 - Acute Megakaryocytic Leukemia.

  • Predominant cells – megakaryocytes.
  • Pancytopenia.
  • Peripheral blood - undifferentiated blasts and megakaryocyte fragments.
  • Bone marrow - 30 percent or more of blasts are megakaryoblasts.


Myelodysplastic Syndromes.

General characteristics:

  • (1) Disorders that result from clonal abnormalities of hematopoietic pluripotent stem cells.
  • (2) Hypercellular bone marrow.
  • (3) Abnormalities in maturation of the following blood cells: Granulocytes, RBCs, megakaryocytes, monocytes.
  • (4) Referred to as “preleukemia.”

FAB classification.

  • RA - refractory anemia. Anemia with oval macrocytes, decreased hemoglobin levels caused by an impaired release of erythrocytes from the bone marrow.
    • Peripheral blood - Less than 1 percent blasts and decreased reticulocyte count.
    • Bone marrow - Less than 5 percent myeloblasts and less than 15 percent of erythroblasts are ringed sideroblasts.
  • RARS - refractory anemia with ringed sideroblasts. Similar to refractory anemia.
    • Peripheral blood – hypochromic microcytes and ovalomacrocytes.
    • Bone marrow - 15 percent or more of NRBC’s are ringed sideroblasts (demonstrates failure of cell to incorporate iron into hemoglobin molecule).
  • RAEB - refractory anemia with excess blasts.
    • Abnormalities in RBCs, granulocytes, and platelets - abnormalities more severe than in RA or RARS.
    • Peripheral blood - Less than 5 percent myeloblasts.
    • Bone marrow – 5 to 20 percent myeloblasts.
NOTE: This condition is classified as an MDS rather than an ANLL because the percentage of myeloblasts in the bone marrow is between 5 and 20 percent. The cytopenias and dyspoiesis morphology separates RAEB from chronic granulocytic leukemia.
  • RAEB-T - refractory anemia with excess blasts in transformation. Abnormalities in RBCs, granulocytes, and platelets.
    • Peripheral blood - Less than 5 percent blasts.
    • Bone marrow – between 21 to 30 percent myeloblasts, may see Auer rods.
    • Highest rate of progression to ANLL.
NOTE: RAEB-T is the designation used for cases in which many of the morphologic features suggest a diagnosis of ANNL but the percentage of bone marrow myeloblasts is less than 30 percent.
  • (CMML - chronic myelomonocytic leukemia. Abnormalities in RBCs, granulocytes, and platelets. Similar to RAEB but with an increase in promonocytes.
    • Peripheral blood.
    • Less than 5 percent blasts.
    • Monocytosis.
    • WBC count greater than 1000 x 109/L.
    • Bone marrow.
    • 5 to 20 percent myeloblasts.
    • Increased serum and urine lysozyme (muramidase) levels due to release of enzyme from monocyte and neutrophil granules.


The general characteristics of chronic myeloproliferative disorders are:

  • Acquired malignant disorder.
  • Develop from the proliferation of an abnormal pluripotent stem cell.
  • Excessive production of normal-appearing mature cells.
  • Specific classification depends on the predominant cell type involved.
  • Asymptomatic or fever, general weakness, bleeding, splenomegaly.
  • Usually affect middle-aged to older people.
  • Acute leukemia is usually the end stage.


Chronic Myelocytic Leukemia (CML). General causes:

  • Stem cell disorder affecting the granulocytic, monocytic, erythrocytic, and megakaryocytic cell lines.
  • Philadelphia chromosome (Ph1) - translocation of long arm of chromosome 22 to long arm of chromosome 9, present in 70 to 90 percent of CML patients.
  • Laboratory findings on the peripheral smear:
    • RBCs - normocytic/normochromic anemia, NRBCs, anisocytosis, basophilic stippling.
    • Platelets - increased or decreased, may have giant platelets and megakaryocytic fragments.
    • WBCs -Moderately to markedly elevated, usually 50 to 300 X 109 WBCs/L at time of diagnosis. Myeloblasts to mature neutrophils present with a predominance of myelocytes and segmented neutrophils. Increased eosinophils and basophils (may see increased blood histamine levels). Frequently, leukocyte and platelet counts are inversely related: the higher the leukocyte count, the lower the platelet count.
  • This effect is probably due to a squeezing out of marrow megakaryocytes by the over abundance of granulocytic cells. Bone marrow with myeloid hyperplasia and increased M:E ratio (10:1). Majority of patients die of complications (infection and/or hemorrhage) associated with blast crisis - blast crisis is usually myeloid but may be lymphoid.
  • In blast phase, 60 percent of cell lines are myeloid. Lymphoblastic characteristics are seen in 25 to 30 percent of patients. Four percent have both lymphoid and myeloid markers, and the remainders are undifferentiated.

Idiopathic Myelofibrosis. Arises from a stem cell defect resulting in an abnormal proliferation of granulocytes, erythrocytes and megakaryocytes. Characterized by:

  • Bone marrow fibrosis - proliferation of fibroblasts produce increased collagen in reaction to abnormal cells.
  • Extramedullary hematopoiesis or myeloid metaplasia of the spleen and liver.
  • Granulocytic and megakaryocytic proliferation in liver and spleen.
  • Leukoerythroblastosis - the presence of both NRBCs and immature neutrophils on the peripheral blood smear.
  • Teardrop cells in the peripheral blood due to passage of RBCs through enlarged spleen.
  • Laboratory findings on the peripheral smear.
    • WBCs: an increased WBC count in 50 percent of patients (most counts less than 30 X 109 WBCs/L but can be as high as 100 X 109 WBCs/L), immature granulocytes, increased basophils.
    • RBCs: teardrop-shaped RBCs, NRBCs, polychromatophilia, reticulocyte count – increased.
    • Platelets- platelet count - increased in about 50 percent of cases initially, but decreases as disease progresses, dwarf megakaryocytes or small megakaryoblasts often present, large, bizarre platelets, platelet dysfunction in up to 50% of patients. Premature death of defective platelets and megakaryocytes causes release of substances from platelet granules which stimulate growth of marrow fibroblasts - results in an increase in fibrous tissue.
  • May transform into acute leukemia.

Essential Thrombocythemia. Caused by megakaryocytic hyperplasia in the bone marrow.

  • Megakaryocytes larger than normal and may be dysplastic in appearance.
  • Laboratory findings on the peripheral smear.
    • Platelets- marked thrombocytosis - platelet count 600 - 2500 X 109/L, giant platelets, microthrombocytes, platelet aggregates, abnormally granulated platelets, and megakaryocytic cytoplasmic fragments, and abnormal platelet function.
    • RBCs - normochromic, normocytic anemia; Howell-Jolly bodies, Pappenheimer bodies, target cells, acanthocytes.
    • Increased WBC count in 1/3 of patients.

Lymphoproliferative Disorders--Acute Lymphoblastic Leukemia (ALL). Replacement of normal hematopoietic elements in the bone marrow by abnormal lymphoid cells. Results in decreased RBCs, phagocytes, and platelets.

  • General characteristics. Symptoms include lethargy, malaise, fever, and infection; many have bone pain in joints/extremities, bleeding problems.
  • Most common malignant disease in children. Most frequently occurs between the ages of 2 and 10.
NOTE: Ninety percent of childhood leukemias in Western culture are the acute lymphoblastic variety.


L1 - small, homogenous lymphoblasts.

  • Nucleus-round, regular in shape, not visible or inconspicuous nucleoli.
  • Cytoplasm- scanty amount, moderately basophilic.
  • Most common type of ALL found in children, responds best to therapy.

L2 - large, heterogenous lymphoblasts.

  • Nucleus-irregular, often clefted or indented, large nucleoli present.
  • Cytoplasm- abundant, basophilic, primarily a disease of older children and adults.
NOTE: This type accounts for 14 percent of childhood ALL cases and includes 64 percent of adult cases.

L3 - “Burkitt's type” – large, homogenous lymphoblasts.

  • Nucleus- oval to round with fine chromatin structure, one or more prominent nucleoli.
  • Cytoplasm- moderately abundant, intensely basophilic, often with prominent vacuoles.
  • Laboratory findings:
  • WBCs-count elevated in 60 to 70 percent of patients (50-100 X 109/L), 50 percent of patients - blast forms predominate, and close to 100 percent lymphoblasts and lymphocytes.
  • Severe normocytic/normochromic anemia, decreased reticulocyte count.
  • Moderate to marked thrombocytopenia.
  • Lymphoblasts may be found within spinal fluid samples.
  • Causes of death - infection and bleeding.
NOTE: This type accounts for about two percent of ALL cases and has a poor prognosis.

Immunological marker classification.

  • Used to divide ALL into subtypes.
  • Based on specific cell markers on the cell membrane of the blasts.
    • Surface immunoglobulins.
    • Cytoplasmic immunoglobulins.
    • HLA surface antigens.
    • Surface markers detected with monoclonal antibodies.


Chronic Lymphoproliferative Disorders. Ninety-nine percent of these leukemias are clonal B-lymphocyte diseases. Proliferation and accumulation of clones of malignant B lymphocytes in the blood, bone marrow, lymph nodes, or other organs. Reduced rate of cell death (rather than an increased rate of cell production) appears to account for the accumulation of these cells. Symptoms include weakness, fatigue, weight loss, enlargement of spleen and/or lymph nodes.

  • A much smaller number of these leukemias are caused by T-lymphocyte proliferation.
  • It is important to distinguish B-cell malignancies from those caused by T cells, because patients with T-cell disease tend to have a more aggressive disease and poorer response to therapy.

Chronic Lymphocytic Leukemia (CLL). Predominant cells - small mature lymphocytes (60 to 95 percent) which may show a small cleft or indentation in the nucleus. Often see smudge cells on peripheral smear - lymphocytes are more fragile than normal so they easily rupture during preparation. The WBC count - increased (20 to 200 X 109/L), and the RBC morphology displays a normocytic/normochromic anemia with normal or slightly decreased platelet count. Ninety percent of patients are over 50 years old.

NOTE: Cytogenetic abnormalities have been noted in 50 percent of CLL cases.

Prolymphocytic Leukemia (PLL). Predominant cells – prolymphocytes. Lymphocytosis exceeding 100 X 109 WBCs/L, anemia and thrombocytopenia.

Hairy Cell Leukemia. Predominant cells - "hairy cells" (medium-sized lymphocytes 15 to 30 mm in diameter, the nucleus is round to oval with fine chromatin, with one to five distinct nucleoli, and a moderate amount of cytoplasm with hair-like or ruffled projections).

Pancytopenia. Chronic, malignant lymphoproliferative disorder.


Malignant tumors of lymphoid tissue (lymph nodes and spleen).

During advanced stages, malignant cells may spill into the blood circulation.

Malignant lymphoma in which the cells reacting to the neoplasm (Reed Sternberg cells) predominant rather than the neoplastic cells.

Moderately increased WBC count with monocytosis, neutrophilia, and variable eosinophilia; toxic granulation; large, bizarre platelets.

  • Hodgkin's disease (HD) -- painless enlargement of lymph node. This disorder distinguished from other lymphomas by the presence of the Reed-Sternberg cell.
  • Non-Hodgkin's lymphoma (NHL) -- painless lymph node enlargement. There is a proliferation of malignant lymphocytes arrested at certain stages of maturation, and abnormal lymphocytes (lymphoma cells) may be present on the peripheral smear.
  • Sézary syndrome -- condition affects the skin and may also involve the lymph nodes, liver, spleen, and lungs. Sézary cells are present in peripheral blood (larger than normal lymphocytes with scant cytoplasm and a cerebriform nucleus with or without nucleoli and with fine chromatin).
  • Reed-Sternberg cells are large and variable in size, 50 to 100 um. The cells often have two or more nuclei with large prominent, round or oval nucleolus and abundant purple-pink cytoplasm.
  • Together, Hodgkin’s disease and non-Hodgkin’s lymphoma are the seventh most common cause of death from cancer in the United States.


Plasma Cell Disorders. Malignant disorders of differentiated end cells of B-lymphocytes. “monoclonal gammopathies” - malignant plasma cells all producing identical proteins.

 Multiple Myeloma (Plasma Cell Myeloma). Patients from 50 to 75 years old with bone pain, weakness, and fatigue. There is a malignant proliferation of atypical and immature forms of plasma cells, occurring in the bone marrow and increased plasma proteins. This disorder may impair function of platelets and interfere with coagulation factors to produce clotting abnormalities. There will be an increased ESR - may be greater than 100 mm/hr, Bence-Jones protein present in urine (increased production of light, monoclonal chains), increased albumin and gamma globulins on serum protein electrophoresis, and a moderate normocytic/normochromic anemia. The peripheral blood smear may show bluish tinge due to increased plasma proteins, marked rouleaux, myeloma cells (morphologically abnormal plasma cells) may be present (usually show bizarre abnormalities: eccentric round nucleus with one or two nucleoli, and multinucleated or lobulated nuclei). There will also be Russell bodies (red granules) in cytoplasm - represent accumulation of IgG in the sacs of the RER, and Mott cells, grape cells, or morula cells (plasma cells containing numerous Russell bodies), and flame cells with pinkish-red colored cytoplasm (represents an accumulation of IgA glycoprotein). The most common cause of death - bacterial infection due to lowered production of normal immunoglobulins. Patients treated with chemotherapy have a significant risk of developing acute myelogenous leukemia (AML).

 Plasma Cell Leukemia. Found only as a terminal stage in multiple myeloma.

  • Greater than 2 X 109 abnormal plasma cells/L, appear small with little cytoplasm and pronounced nuclear: cytoplasmic asynchronism.
  • Moderate to marked anemia and thrombocytopenia in 70 percent of patients.
  • WBC count - slight to moderate elevation.

Waldenström’s Macroglobulinemia. Symptoms include weakness, fatigue, bleeding, enlarged lymph nodes and spleen. This is caused by an infiltration of the bone marrow with a clone of B-lymphocytes in an intermediate stage of development between mature lymphocytes and early plasma cells. These patients develop macroglobulin (monoclonal IgM immunoglobulins of high molecular weight) - hyperviscosity syndrome. There is a normocytic, normochromic anemia present, thrombocytopenia, abnormal platelet function, abnormal coagulation studies, marked rouleaux on peripheral smear, increased ESR, and increased plasma viscosity.


David L. Heiserman, Editor

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Revised: June 06, 2015