Abstract
The chronic myeloid leukemias are a group of hematological neoplasms resulting from mutation in either a pluripotent (lymphoid-myeloid) stem cell or in a multipotent myeloid progenitor or stem cell. The former group of leukemias are actually, or potentially, of mixed phenotype while the latter have a purely myeloid phenotype.
Keywords
Introduction
The chronic myeloid leukemias are a group of hematological neoplasms resulting from mutation in either a pluripotent (lymphoid-myeloid) stem cell or in a multipotent myeloid progenitor or stem cell. The former group of leukemias are actually, or potentially, of mixed phenotype while the latter have a purely myeloid phenotype.
Diagnosis of these conditions is based on clinical and hematological features with genetic analysis being crucial for the recognition of some categories. Genetic analysis has been incorporated, as far as current knowledge permits, into the classification of the chronic myeloid leukemias, in the 2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [1]. Depending on their typical hematological features and any relevant genetic abnormality, they are assigned to the categories: (a) myeloproliferative neoplasm; (b) myelodysplastic/myeloproliferative neoplasm; and (c) myeloid or lymphoid neoplasm with rearrangement of PDGFRA, PDGFRB or FGFR1.
In making a morphological diagnosis, the peripheral blood features are often of critical importance. The bone marrow aspirate and trephine biopsy sections give useful supplementary information. Flow cytometric immunophenotyping is only of diagnostic importance when there is presentation with acute phase disease or when acute transformation subsequently occurs. Immunohistochemistry on trephine biopsy sections can be useful, particularly in the recognition of dysplastic megakaryocytes and for confirmation of the presence of dysplastic mast cells. Cytochemistry is now of little importance in diagnosis; the neutrophil alkaline phosphatase score is redundant when genetic analysis is available and immunophenotyping is superior to cytochemistry for the recognition of the lineage involved in acute transformation.
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) results from a mutation in a pluripotent hematopoietic stem cell that results in formation of a BCR-ABL1 fusion gene [2]. The associated acquired cytogenetic abnormality is usually t(9;22)(q34;q11.2), but there are other mechanisms, including variant and complex translocations (see Chap. 6). The derivative chromosome 22 is known as the Philadelphia (Ph) chromosome. Alternative designations of this condition are chronic granulocytic leukemia and chronic myeloid leukemia, but it should be noted that the latter term, although very widely used, is open to misinterpretation since it is also used as a generic term for all the chronic myeloid leukemias.
This disease occurs at all ages, but incidence increases steadily with age and is somewhat higher in men than in women. Common clinical features are weight loss, low-grade fever, sweating, splenomegaly, and, when disease is advanced, hepatomegaly [3]. Lymphadenopathy is only a feature when acute transformation occurs. Patients with a very high white cell count can have features of leucostasis, such as blurred vision and priapism. Many patients are now diagnosed as a result of an incidental blood count when they are asymptomatic.
The natural history of CML is that the chronic phase of the disease is followed by acute transformation (myeloid, lymphoid, or mixed), which may be preceded by an accelerated phase. The abrupt onset of acute transformation without a preceding accelerated phase is more common in lymphoid transformation.
Peripheral Blood Count and Cytology
The peripheral blood count in chronic phase CML typically shows leukocytosis and anemia. Usually there is also thrombocytosis although the platelet count can be normal or reduced. Some patients have thrombocytosis without leucocytosis. Such BCR-ABL1-positive cases should be recognized as a variant of CML [2]. The blood film characteristically shows a particular increase in myelocytes and neutrophils (Fig. 3.1). Basophils are almost invariably increased and eosinophils usually so [4]. Eosinophil and basophil myelocytes may also be present. The absolute monocyte count is increased but not in proportion to the increase in granulocytes. The number of blast cells and promyelocytes is proportionate to the number of myelocytes. Cells of the granulocyte lineages do not show dysplastic features. Platelets show anisocytosis with some giant forms. There may be occasional circulating megakaryocyte nuclei with scanty cytoplasm (‘bare’ megakaryocyte nuclei). Red cells may show nonspecific abnormalities, such as anisocytosis and mild poikilocytosis. There may be circulating nucleated red blood cells. Neutrophil alkaline phosphatase is reduced in the great majority of patients, but this test is redundant when cytogenetic and molecular analyses are available.
Peripheral blood features of the accelerated phase of CML may include: leucocytosis or thrombocytosis that is refractory to treatment; an increasing basophil count; a disproportionate increase in blast cells; the appearance of dysplastic features such as hypolobulated neutrophils and circulating micromegakaryocytes; thrombocytopenia; and increasing anemia. A disproportionate increase in eosinophils can occur but is much less common than marked basophilia. Poikilocytosis may become more marked and there may be teardrop poikilocytes.
In blast transformation there is usually an increase in blast cells in the peripheral blood (Fig. 3.2). Usually these are myeloblasts, megakaryoblasts, or lymphoblasts. When transformation is megakaryoblastic, there may also be circulating micromegakaryocytes. Less common forms of transformation (determined by the underlying further mutations that have occurred) include monoblastic, eosinophilic, erythroblastic, and hypergranular promyelocytic.
Bone Marrow Cytology
The bone marrow aspirate in chronic phase CML shows marked hypercellularity due to an increase in granulocytes and their precursors (Fig. 3.3). The myeloid:erythroid ratio is almost always greater than 10:1 and often of the order of 25:1. Megakaryocytes are usually increased with a tendency to be smaller than normal with reduced nuclear lobulation, reflecting a decrease in ploidy. However, micromegakaryocytes, such as those seen in the myelodysplastic syndromes, are not a feature of chronic phase disease. Sometimes there is an increase in storage cells—pseudo-Gaucher cells and sea blue histiocytes.
In the accelerated phase, the aspirate may show increased blast cells, increased basophils, and dysplastic features in the cells of any lineage.
In blast transformation, the bone marrow shows increased blast cells, except in the minority of cases in which transformation is first detected at an extramedullary site. Myeloblasts are often agranular and Auer rods are usually absent. In the case of myeloid or mixed lineage transformation, there are usually dysplastic features, particularly in the megakaryocyte lineage (Fig. 3.4).
Flow Cytometric Immunophenotyping
Immunophenotyping is not diagnostically useful in chronic phase disease.
Genetics
Cytogenetic and genetic features are discussed in Chap. 6.
Histology
In chronic phase CML, trephine biopsy sections show an increase in cells of all granulocyte lineages but, apart from the loss of fat cells, with retention of normal bone marrow architecture (Fig. 3.5) [5–7]. There is an expansion of the band of myeloblasts and promyelocytes that is usually detected against the bony spicule and around arterioles. Eosinophils are readily detected, but basophils are not specifically identifiable on hematoxylin and eosin (H&E) stains as granules are dissolved during processing. Megakaryocytes are increased in number with a reduction in average size and nuclear lobulation. They are normally located and do not form large clusters. Erythropoiesis is decreased. Mast cells and plasma cells are often increased. Increased storage cells may be apparent (Fig. 3.6). Bone marrow vascularity is increased (neoangiogenesis). Reticulin is usually normal or only mildly increased.
In accelerated phase, the changes that would be expected from the bone marrow aspirate are present. In addition, the bone marrow architecture may be abnormal, e.g., with megakaryocytes located adjacent to bony spicules or forming large clusters. Intravascular hemopoiesis and bone marrow necrosis can occur. Reticulin may be increased. Sometimes the increase in reticulin is marked and there is also collagen fibrosis and osteosclerosis (Fig. 3.7).
Immunohistochemistry with CD42b or CD61 monoclonal antibodies can be used to identify dysplastic megakaryocytes. CD34 antibodies can identify blast cells and the endothelial cells of new vessels.
In blast transformation, there is an increase in the blast cells of one or more lineages. In myeloid transformation, there can also be a marked increase of dysplastic megakaryocytes, often in large clusters or sheets. The pattern of blast infiltration may initially be random focal, but subsequently blast cells obliterate maturing hematopoietic cells. Reticulin and collagen fibrosis are common, particularly when there is an increase in megakaryoblasts and dysplastic megakaryocytes.
Immunohistochemistry can be used to identify myeloblastic crisis (CD68, lysozyme), megakaryoblastic crisis (CD42b, CD61), erythroblastic crisis (antiglycophorin—CD235a or CD236R), and B-lymphoblastic crisis (CD79a is more generally positive than CD20). CD34 immunohistochemistry can help in the quantification of blast cells.
In extramedullary transformation, there is initially infiltration of another tissue or organ, e.g., a lymph node, with subsequent spread to the marrow. In extramedullary transformation, immunohistochemistry is useful for confirmation of the diagnosis.
Atypical (Ph-Negative) Chronic Myeloid Leukemia
Atypical chronic myeloid leukemia (aCML) is an uncommon, Ph-negative, BCR-ABL1-negative chronic myeloid leukemia, which is categorized in the WHO classification as an MDS/MPN [8–10]. Clinical features are similar to those of CML, but the prognosis is worse. Death may result from bone marrow failure or evolution to acute myeloid leukemia (AML). Atypical CML is mainly a disease of adults, particularly elderly adults with a similar incidence in men and women
Peripheral Blood Count and Cytology
The peripheral blood shows leukocytosis and anemia (Fig. 3.8). There may be anisocytosis, poikilocytosis, macrocytosis, or dimorphism. The platelet count is often reduced but may be normal or increased. In comparison with CML, anemia tends to be more severe and thrombocytopenia more common. There is an increase in neutrophils and their precursors. Eosinophils and basophils are often increased but less consistently than in CML. However, some patients have prominent eosinophilia. The monocyte count is relatively higher than in CML; it may be more than 1 × 109/l, but monocytes are not usually more than 10 % of leucocytes. Granulocyte precursors are also present. In comparison with chronic myelomonocytic leukemia, promyelocytes, myelocytes, and metamyelocytes are at least 10 % of leucocytes and sometimes 15 % or higher. These may include blast cells but, by definition, blast cells (plus promonocytes) are less than 20 % in the blood (and the bone marrow). Dysplastic features are present in neutrophils; hypolobation, abnormal nuclear shapes, increased chromatin clumping, and reduced granularity may be seen. Monocytes may also be dysplastic, showing hyperlobation or hypolobation, increased cytoplasmic basophilia, and increased granularity. The neutrophil alkaline phosphatase score is variable and is not diagnostically useful.
Bone Marrow Cytology
The bone marrow aspirate shows increased cellularity with an increase mainly in neutrophils and their precursors. Monocytes and their precursors may be increased and a nonspecific esterase stain can help in their detection. Megakaryocytes may be present in normal numbers or may be decreased or increased. There is dysplasia, which is often of trilineage. Dysgranulopoiesis is usual, but there may also be ring sideroblasts and other features of dyserythropoiesis, hypolobated megakaryocytes, and micromegakaryocytes.
Flow Cytometric Immunophenotyping
Immunophenotyping is not known to be diagnostically useful.
Genetics
Karyotypic abnormalities are common and can include trisomy 8, 20q–, i(17q) and abnormalities of chromosomes 12, 13, 14, 17, and 19. NRAS. KRAS, CBL, and TET2 may be mutated. Patients with BCR-ABL1 or rearrangement of PDGFRA, PDGFRB, or FGFR1 are specifically excluded from this diagnostic category.
Histology
Cellularity is increased as a result of an increase in neutrophils and precursors and a variable increase in monocyte precursors. There is dysplasia and the architecture is disorganized. Reticulin may be increased and collagen fibrosis and osteosclerosis occasionally occur. Immunohistochemistry is useful to highlight dysplastic megakaryocytes (CD42b and CD61) and increased monocytes (CD14 and CD68R).
Chronic Myelomonocytic Leukemia
This is Ph-negative chronic myeloid leukemia that is categorized in the WHO classification as an MDS/MPN [11, 12]. The most prominent clinical features are anemia and splenomegaly, but skin and lymph node infiltration and pleural, peritoneal, and pericardial effusions can also be seen. It is mainly a disease of the middle aged and elderly and shows a male predominance. Transformation to AML occurs in up to a quarter of the patients.
Peripheral Blood Count and Cytology
The peripheral blood shows a normocytic or macrocytic anemia. Red cells are sometimes dimorphic. Leukocytosis is usual but not invariable. There is monocytosis with, by definition, a monocyte count of more than 1 × 109/l (Fig. 3.9). Neutrophils may be increased, normal, or decreased. Neutrophil precursors may be present but, in contrast to aCML, they are less than 10 % of the cells and usually less than 5 %. There may be small numbers of blast cells and promonocytes; by definition, they total less than 20 % of the cells, but they are usually much less. The number of blast cells (plus promonocytes) in the blood is of prognostic significance and the presence of 5 % or more leads to a classification as CMML-2. A minority of patients have prominent eosinophilia. The platelet count is often reduced but can be normal or high.
Dysplastic features may be present, but are usually less prominent than in aCML. Monocytes may be immature (cytoplasmic basophilia, reduced chromatin condensation, or reduced nuclear lobulation).
Bone Marrow Cytology
The bone marrow shows increased cellularity due to an increase of neutrophils and monocytes and their precursors but a nonspecific esterase stain may be necessary to demonstrate the increase in cells of monocyte lineage. Blasts plus promonocytes are less than 20 %. The number of blast cells (plus promonocytes) in the marrow is of prognostic significance and the presence of 10 % or more leads to the classification as CMML-2. Auer rods are rarely present but, when present, also lead to classification as CMML-2; a myeloperoxidase or Sudan black B stain is useful for their detection. Some patients have an increase of eosinophils and precursors. There is variable dysplasia, which may include ring sideroblasts.
Flow Cytometric Immunophenotyping
Immunophenotyping may show monocytes to be phenotypically abnormal with reduced, increased, or aberrant expression of various antigens. An abnormal phenotype may be the result of immaturity of monocytes (e.g., reduced CD14 expression) or of aberrant antigen expression (e.g., expression of CD2).
Genetics
Karyotypic abnormalities are detected in a quarter to a half of patients. They include trisomy 8, monosomy 7, del(7)(q) and rearrangements with a 12p breakpoint. Common molecular changes include mutations of RAS group genes, RUNX1, TET2, and CBL. By definition, BCR-ABL1 and rearrangement of PDGFRA and PDGFRB are absent.
Histology
Trephine biopsy sections show the changes that would be expected from the aspirate. Hypercellularity is usual and results from an increase in the cells of both neutrophil and monocyte lineages. Immunohistochemistry (CD14, CD68R, or CD163) may be necessary to demonstrate the increase in the cells of monocyte lineage. Erythropoiesis may be quantitatively normal or increased. There may be nodules of plasmacytoid dendritic cells, confirmed by immunohistochemistry for CD4, CD14, CD68R, and CD123 [13, 14]. Reticulin deposition is often increased.
Chronic Eosinophilic Leukemia
Chronic eosinophilic leukemias, in the WHO classification, are categorized either as chronic eosinophilic leukemia (CEL), not otherwise specified [15], or as chronic myeloid or lymphoid neoplasm associated with rearrangement of PDGFRA, PDGFRB, or FGFR1 [16–18]. Diagnosis and categorization requires both cytogenetic and molecular analyses, the latter to detect the most frequent rearrangement of PDGFRA, a FIP1L1-PDGFRA fusion gene resulting from a cryptic deletion at 4q12. Diagnosis of CEL requires an eosinophil count of at least 1.5 × 109/l and some evidence that the process is leukemic in nature, such as a clonal cytogenetic or molecular abnormality or an increase in blast cells.
Leukemias with rearrangement of PDGFRA can present as CEL, AML with eosinophilia, or T-lineage acute lymphoblastic leukemia (ALL) with eosinophilia [17, 19]. Leukemias with rearrangement of PDGFRB can present as CEL or as either CMML or aCML with eosinophilia. Leukemias with rearrangement of FGFR1 can present as CEL, AML with eosinophilia, or acute lymphoblastic leukemia/lymphoma (ALL) with eosinophilia; ALL is most often of T lineage but can be of B lineage [17]. In all these disorders, patients who present with chronic phase disease can subsequently suffer acute transformation.
Clinical presentation can be with features suggestive of leukemia (such as anemia, splenomegaly, and sometimes lymphadenopathy) or features reflecting tissue damage by eosinophils (such as cardiac, respiratory, and neurological symptoms). CEL associated with FIP1L1-PDGFRA shows a remarkable male predominance. CEL associated with PDGFRB or FGFR1 rearrangement is also more common in males. CEL associated with rearrangement of PDGFRA or PDGFRB is sensitive to imatinib and making these specific diagnoses is therefore important.
Elevation of serum vitamin B12 and serum tryptase is usual in patients with CEL associated with FIP1L1-PDGFRA.
Peripheral Blood Count and Cytology
The peripheral blood shows an increase in eosinophils, which may be cytologically fairly normal or may show reduced or increased nuclear lobulation, loss of granules, darkly staining (purple) granules, or cytoplasmic vacuolation (Fig. 3.10). There may be eosinophil precursors and blast cells. By definition, blast cells are less than 20 %. Some patients also have an increase in neutrophils or monocytes, anemia, or thrombocytopenia.
Bone Marrow Cytology
The bone marrow shows an increase in eosinophils and their precursors plus a variable increase in precursors of monocytes and neutrophils. Blast cells may be increased but are less than 20 %.
Flow Cytometric Immunophenotyping
Immunophenotyping is occasionally needed to show the lineage of blast cells and thus distinguish CEL from ALL with reactive eosinophilia. However, it must be noted that in the case of CEL associated with rearrangement of PDGFRA or FGFR1, there may be either presentation as ALL or a lymphoblastic transformation; usually but not invariably the lymphoid component is of T lineage.
Genetics
Karyotypic analysis may show t(5;12)(q31∼q33;p12) or another translocation with a 5q31-32 breakpoint involving PDGFRB. Rarely there is a translocation with a 4q12 breakpoint involving PDGFRA, but usually rearrangement of this gene is cryptic. Another translocation specifically associated with CEL is t(8;9)(p21-23;p23-24) leading to a PCM1-JAK2 fusion gene. Other nonspecific chromosomal abnormalities may be found including trisomy 8, del(20)(q), monosomy 7, and i(17)(q). The demonstration of t(8;21)(q22;q22), inv(16)(p13.1q22), or t(16;16)(p13.1;q22) excludes a diagnosis of CEL and leads to a diagnosis of AML.
The most important molecular abnormality that must be sought in suspected CEL is the FIP1L1-PDGFRA fusion gene, which can be demonstrated either by fluorescence in situ hybridization (FISH) analysis or by PCR (nested PCR often being needed) [16]. Occasionally patients with FIP1L1-PDGFRA-associated CEL develop a further mutation in the fusion gene, sometimes associated with imatinib resistance or transformation to AML [19].
Histology
Trephine biopsy sections show the expected increase in eosinophils and precursors and a variable increase in the cells of neutrophil or monocyte lineages. Charcot–Leyden crystals are also sometimes seen [20]. Cases associated with rearrangement of PDGFRA or PDGFRB may show an increase of mast cells, which are sometimes spindle shaped and clustered. Their presence can be highlighted by immunohistochemistry for mast cell tryptase. The mast cells may show aberrant expression of CD25 and sometimes of CD2, whereas the neoplastic cells of systemic mastocytosis usually show aberrant expression of both CD2 and CD25.
Chronic Neutrophilic Leukemia
Chronic neutrophilic leukemia is a rare myeloproliferative neoplasm that occurs mainly in adults [21]. It is characterized by increased neutrophil production, splenomegaly, and sometimes hepatomegaly. Transformation to AML can occur and at this stage the neutrophil count may fall [22].
Peripheral Blood Count and Cytology
There is leucocytosis and neutrophilia (Fig. 3.11). The WHO classification requires a white cell count of at least 25 × 109/l for this diagnosis. Neutrophils may be heavily granulated, but otherwise there are no dysplastic features and there are only small numbers of neutrophil precursors. With disease progression there may be anemia and thrombocytopenia.
Bone Marrow Cytology
The bone marrow aspirate shows an increase of neutrophils and their precursors without dysplastic features or any increase in the blast cells. The bone marrow must be carefully examined to exclude a plasma cell neoplasm since reactive neutrophilia due to multiple myeloma is an important differential diagnosis.
Flow Cytometric Immunophenotyping
Immunophenotyping has no role in diagnosis.
Genetics
Cytogenetic analysis is usually normal. A minority of patients have karyotypic abnormalities typical of myeloid neoplasms such as trisomy 8, trisomy 9, trisomy 21, del(11)(q), del(12)(p), or del(20)(q). Sometimes an initially normal karyotype becomes abnormal, with acute transformation [22]. There is no recognized recurrent genetic abnormality. Occasional patients have a JAK2 V617F mutation, which may be homozygous [23]. By definition, there is no BCR-ABL1 fusion gene.
Histology
Trephine biopsy sections show increased granulopoiesis.
Juvenile Myelomonocytic Leukemia
This is a rare myelodysplastic/myeloproliferative neoplasm of children [24–29]. Peak incidence is under the age of 3 years and the condition is more common in boys. Predisposing conditions include neurofibromatosis type 1 (NF1 mutated) and Noonan syndrome (PTPN11 mutated). Clinical features can include fever, cough, splenomegaly, hepatomegaly, often lymphadenopathy, skin lesions (an eczematous or maculopapular rash or xanthomas), and a bleeding tendency. Respiratory tract infections are common. In patients with underlying neurofibromatosis there may be café-au-lait spots whereas patients with Noonan syndrome have facial dysmorphism and congenital cardiac anomalies. A hallmark of the disease is increased sensitivity in vitro to granulocyte macrophage-colony stimulating factor as a result of increased signaling through the RAS-MAPK pathway. The rate of disease progression is quite variable, but prognosis is generally poor unless hematopoietic stem cell transplantation is carried out. Transformation to AML occurs in about 15 % of the patients [28]. Occasional patients have had transformation to B-cell precursor ALL and the same acquired genetic lesion has sometimes been found in T-lymphoid and myeloid cells, suggesting that the leukemic clone may be derived from a pluripotent lymphoid-myeloid stem cell [28].
Peripheral Blood Count and Cytology
The peripheral blood shows leucocytosis, monocytosis, and neutrophilia with a lesser increase in granulocyte precursors (Fig. 3.12). Eosinophilia and basophilia are less common than neutrophilia. There is a variable degree of dysplasia. Blast cells (plus promonocytes) are usually low and, by definition, never more than 20 %. Anemia and thrombocytopenia are usual. There may be circulating nucleated red blood cells and some patients have macrocytosis. There is often increased rouleaux formation.
Blood tests show other abnormalities. Polyclonal hypergammaglobulinaemia is common and the erythrocyte sedimentation rate is increased. There may be autoantibodies including anti-erythrocyte antibodies. The hemoglobin F percentage is usually increased in comparison with age-matched healthy children and there may be other features suggesting reversion to fetal-type erythropoiesis, such as increased expression of the i antigen and decreased expression of the I antigen, carbonic anhydrase, and hemoglobin A2.
Bone Marrow Cytology
The bone marrow is hypercellular as a result of increased granulopoiesis. Blast cells (plus promonocytes) are less than 20 %. Megakaryocytes are often reduced.
Flow Cytometric Immunophenotyping
Immunophenotyping is not diagnostically useful.
Genetics
There is no specific chromosomal abnormality and cytogenetic analysis is often normal. Some patients have monosomy 7, trisomy 8, or a complex karyotypic abnormality. Chromosomal analysis may be initially normal but become abnormal during the course of the illness. Genetic analysis shows four nonoverlapping groups of patients with loss-of-function mutation in NF1 (inherited or acquired) or mutation in PTPN11 (inherited or acquired) [30], CBL [31], or a RAS group gene (NRAS or HRAS) [32]. In children with neurofibromatosis there may be homozygosity for the mutant gene as a result of acquired uniparental disomy or there may be somatic mutation in the initially normal allele [33, 34].
Histology
The bone marrow is hypercellular as a result of increased granulopoiesis and a variable increase in monocytopoiesis and erythropoiesis. Reticulin may be increased.
Conclusions
The chronic myeloid leukemias are a heterogeneous group of hematopoietic neoplasms, some with mainly proliferative features and others with myelodysplastic/myeloproliferative characteristics. Origin may be in a pluripotent lymphoid-myeloid stem cell or in a committed myeloid cell. Since leukemias with a BCR-ABL1 fusion gene or rearrangement of PDGFRA or PDGFRB are sensitive to tyrosine kinase inhibitors, precise diagnosis is of considerable importance.
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Bain, B.J. (2013). Pathology of the Chronic Myeloid Leukemias. In: Wiernik, P., Goldman, J., Dutcher, J., Kyle, R. (eds) Neoplastic Diseases of the Blood. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3764-2_3
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