Pathology
CHRONIC LEUKEMIA
Leukemia is cancer that starts in the blood-forming cells of the bone marrow. When one of these cells changes and becomes a leukemia cell, it no longer matures the way it should and grows out of control. Often, it divides to make new cells faster than normal. Leukemia cells also don't die when they should. This allows them to build up in the bone marrow, crowding out normal cells. At some point, leukemia cells leave the bone marrow and spill into the bloodstream. This increases the number of white blood cells in the blood. Once in the blood, leukemia cells can spread to other organs, where they can prevent other cells in the body from functioning normally.
Leukemia is different from other types of cancer that start in organs like the lungs, colon, or breast and then spread to the bone marrow. Cancers that start elsewhere and then spread to the bone marrow are not leukemia.
What is a chronic leukemia?
In chronic leukemia, the cells can mature partly (and more are like normal white blood cells). but not completely. These cells may look fairly normal, but they're not. They generally don't fight infection as well as normal white blood cells do. The leukemia cells survive longer than normal cells, and build up, crowding out normal cells in the bone marrow. It can take a long time before chronic leukemias cause problems, and most people can live with them for many years. But chronic leukemias tend to be harder to cure than acute leukemias.
Acute myeloid leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow
Pathophysiology
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation or inactivation of genes through chromosomal translocations and other genetic and/or epigenetic abnormalities.
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of the abnormal myeloblasts, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.
Etiology
Acute myeloid leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. (See Pathophysiology.) Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor. (See Etiology.)
Patients with AML present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. (See Presentation.) The workup for AML includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), and analysis of genetic abnormalities. (See Workup.)
Current standard chemotherapy regimens cure only a minority of patients with AML. Consequently, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. (See Treatment.) Readmission is frequently required for the management of toxic effects of chemotherapy.
Pathophysiology
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation or inactivation of genes through chromosomal translocations and other genetic and/or epigenetic abnormalities.
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of the abnormal myeloblasts, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.
Etiology
Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor.
Antecedent hematologic disorders
The most common risk factor for AML is the presence of an antecedent hematologic disorder, the most common of which is myelodysplastic syndrome (MDS). MDS is a bone marrow disease of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years. Patients with low-risk MDS (eg, MDS with ringed sideroblasts) generally do not develop AML, whereas patients with high-risk MDS (eg, MDS with excess blasts) frequently do.
Other antecedent hematologic disorders that predispose patients to AML include aplastic anemia and myeloproliferative disorders, especially myelofibrosis.
GENETICS
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis. Usually, these patients develop AML during childhood; rarely, they may present in young adulthood.
More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H: quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML. [4] Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both.
Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML after chemotherapy for other malignancies.
Acute myeloid leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. (See Pathophysiology.) Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor. (See Etiology.)
Patients with AML present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. (See Presentation.) The workup for AML includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), and analysis of genetic abnormalities. (See Workup.)
Current standard chemotherapy regimens cure only a minority of patients with AML. Consequently, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. (See Treatment.) Readmission is frequently required for the management of toxic effects of chemotherapy.
Pathophysiology
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation or inactivation of genes through chromosomal translocations and other genetic and/or epigenetic abnormalities.
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of the abnormal myeloblasts, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.
Etiology
Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor.
Antecedent hematologic disorders
The most common risk factor for AML is the presence of an antecedent hematologic disorder, the most common of which is myelodysplastic syndrome (MDS). MDS is a bone marrow disease of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years. Patients with low-risk MDS (eg, MDS with ringed sideroblasts) generally do not develop AML, whereas patients with high-risk MDS (eg, MDS with excess blasts) frequently do.
Other antecedent hematologic disorders that predispose patients to AML include aplastic anemia and myeloproliferative disorders, especially myelofibrosis.
GENETICS
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis. Usually, these patients develop AML during childhood; rarely, they may present in young adulthood.
More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H: quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML. [4] Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both.
Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML after chemotherapy for other malignancies.
Treatment of Acute Myeloid Leukemia
Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.
CML accounts for 20% of all leukemias affecting adults. See the image below.Pathophysiology
CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)].
The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome after the city of discoverThis translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood
Diagnosis
The diagnosis of CML is based on the following:
Histopathologic findings in the peripheral blood
Philadelphia chromosome (Ph1) in bone marrow cells
The workup for CML consists of the following:
CBC with differential
Peripheral blood smear
Bone marrow analysis
Blood count and peripheral smear findings
Total WBC count 20,000-60,000 cells/μL, with mildly increased basophils and eosinophils
Mild to moderate anemia, usually normochromic and normocytic
Platelet counts low, normal, or increased
Leukocyte alkaline phosphatase stains very low to absent in most cells
Leukoerythroblastosis, with circulating immature cells from the bone marrow
Early myeloid cells (eg, myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells)
Bone marrow findings
Ph1 (a reciprocal translocation of chromosomal material between chromosomes 9 and 22)
BCR/ABL mutation
Hyper cellularity, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells
Megakaryocytes are prominent and may be increased
Mild fibrosis in the reticulin stain
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (acute lymphocytic leukemia, ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is the most common type of cancer and leukemia in children in the United States. The image below shows B-cell lymphoblastic leukemia/lymphoma (B-ALL).
Pathophysiology
The malignant cells of acute lymphoblastic leukemia (ALL) are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations or abnormalities of chromosome number.
These aberrant lymphoblasts proliferate, reducing the number of the normal marrow elements that produce other blood cell lines (red blood cells, platelets, and neutrophils). Consequently, anemia, thrombocytopenia, and neutropenia occur, although typically to a lesser degree than is seen in acute myeloid leukemia. Lymphoblasts can also infiltrate outside the marrow, particularly in the liver, spleen, and lymph nodes, resulting in enlargement of the latter organs.
Diagnosis of ALL
Laboratory tests and other studies used in the workup for ALL include the following:
Complete blood count with differential
Coagulation studies, including PT, PTT, fibrinogen and fibrin split products
Peripheral blood smear
Chemistry profile, including lactate dehydrogenase, uric acid, liver function studies, and BUN/creatinine
Appropriate cultures (in particular, blood cultures) in patients with fever or other signs of infection
Chest x-ray
Computed tomography, as indicated by symptoms
Multiple-gated acquisition scanning or echocardiogram
Electrocardiography
Lumbar puncture (especially in children)
Bone marrow aspiration and biopsy (definitive for confirming leukemia)
Bone marrow studies should include the following:
Histology
Immunohistochemistry/flow cytometry
Cytogenetics
Fluorescence in situ hybridization
Polymerase chain reaction
Next-generation sequencing
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made.
it typically progresses more slowly than other types of leukemia
Symptoms:
Many people with chronic lymphocytic leukemia have no early symptoms. Those who do develop signs and symptoms may experience:
- Enlarged, but painless, lymph nodes
- Fatigue
- Fever
- Pain in the upper left portion of the abdomen, which may be caused by an enlarged spleen
- Night sweats
- Weight loss
- Frequent infections.
Laboratory findings:
The diagnosis of CLL can usually be made on the basis of physical findings and Blood smear examination-
1. BLOOD PICTURE:the findings of routine blood picture are as follows:
- Anaemia: usually mild to moderate and normocytic normochromic in type.
- white blood cells: Typically there is marked Leucocytosis but less than that seen in CML.Smudge or basket cells( degenerated forms) ar present due to damaged nuclei of fragile malignant lymphocytes.
- platelets: platelets count is normal or moderately reduced as an autoimmune phenomenon.
2. BONE MARROW EXAMINATION:
- Increased lymphocytes count(25-95%)- Reduced myeloid precursors.- Reduced erythroid precursors.
3.LYMPH NODE BIOPSY:
Cases with lymphadenopathy at Presentation show replacement of the lymph node by diffuse proliferation of well differentiated,mature small and uniform lymphocytes without any cytologic atypia.
4. OTHER INVESTIGATIONS:- Erythrocyte rosette test with mouse red is positive in more than 95% of cases.
- positive for B-cell markers typically CD5 Positive.
- serum immunoglobulins level is generally reduced.- coombs test positive in 20% cases.- cytogenetic abnormalities most commonly trisomy 12 seen in about 25% cases.
Pathophysiology
CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)].
This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood
Diagnosis
The diagnosis of CML is based on the following:
Histopathologic findings in the peripheral blood
Philadelphia chromosome (Ph1) in bone marrow cells
The workup for CML consists of the following:
CBC with differential
Peripheral blood smear
Bone marrow analysis
Blood count and peripheral smear findings
Total WBC count 20,000-60,000 cells/μL, with mildly increased basophils and eosinophils
Mild to moderate anemia, usually normochromic and normocytic
Platelet counts low, normal, or increased
Leukocyte alkaline phosphatase stains very low to absent in most cells
Leukoerythroblastosis, with circulating immature cells from the bone marrow
Early myeloid cells (eg, myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells)
Bone marrow findings
Ph1 (a reciprocal translocation of chromosomal material between chromosomes 9 and 22)
BCR/ABL mutation
Hyper cellularity, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells
Megakaryocytes are prominent and may be increased
Mild fibrosis in the reticulin stain
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (acute lymphocytic leukemia, ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is the most common type of cancer and leukemia in children in the United States. The image below shows B-cell lymphoblastic leukemia/lymphoma (B-ALL).
Pathophysiology
The malignant cells of acute lymphoblastic leukemia (ALL) are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations or abnormalities of chromosome number.
These aberrant lymphoblasts proliferate, reducing the number of the normal marrow elements that produce other blood cell lines (red blood cells, platelets, and neutrophils). Consequently, anemia, thrombocytopenia, and neutropenia occur, although typically to a lesser degree than is seen in acute myeloid leukemia. Lymphoblasts can also infiltrate outside the marrow, particularly in the liver, spleen, and lymph nodes, resulting in enlargement of the latter organs.
Diagnosis of ALL
Laboratory tests and other studies used in the workup for ALL include the following:
Complete blood count with differential
Coagulation studies, including PT, PTT, fibrinogen and fibrin split products
Peripheral blood smear
Chemistry profile, including lactate dehydrogenase, uric acid, liver function studies, and BUN/creatinine
Appropriate cultures (in particular, blood cultures) in patients with fever or other signs of infection
Chest x-ray
Computed tomography, as indicated by symptoms
Multiple-gated acquisition scanning or echocardiogram
Electrocardiography
Lumbar puncture (especially in children)
Bone marrow aspiration and biopsy (definitive for confirming leukemia)
Bone marrow studies should include the following:
Histology
Immunohistochemistry/flow cytometry
Cytogenetics
Fluorescence in situ hybridization
Polymerase chain reaction
Next-generation sequencing
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made.
Many people with chronic lymphocytic leukemia have no early symptoms. Those who do develop signs and symptoms may experience:
- Enlarged, but painless, lymph nodes
- Fatigue
- Fever
- Pain in the upper left portion of the abdomen, which may be caused by an enlarged spleen
- Night sweats
- Weight loss
- Frequent infections.
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