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Leukemia algorithm At Cornell University, we generally distinguish three different main types of leukemia: Acute leukemia, chronic leukemia and lymphoma with a leukemic phase. We use a combination of clinical signs, hematologic findings and immunophenotyping/cytochemical results for distinguishing between the types of leukemia (see algorithm). We have also provided this information in an introductory instructional video. Acute leukemiaThese leukemias generally arise primarily in the bone marrow and are due to genetic mutations that prevent cell maturation and promote proliferation. Thus, the neoplastic cells proliferate in and replace the bone marrow, so that normal hematopoietic cells are markedly decreased (called myelophthisis). The leukemic cells can also infiltrate extramedullary sites secondarily (spleen, liver, lymph nodes). The term “acute” applies to the stage of maturation, i.e. immature or precursor cell. In reality, acute leukemias (myeloid or lymphoid) are also acute in terms of chronology (rapid onset) and progression. They are frequently rapidly fatal, responding poorly to therapy (particularly myeloid variants). In general, the tumor cells have fine chromatin (euchromatin) and indistinct nucleoli, i.e. they are called “blasts”. They may or may not show features of differentiation so morphologic features should not be relied upon to differentiate acute myeloid leukemia (AML) from acute lymphoblastic/lymphoid leukemia (ALL) or acute leukemia from immature/precursor/lymphoblastic forms of lymphoma. Animals with acute leukemia usually present with severe cytopenias (because the marrow has been replaced) and many circulating blasts, with mild splenomegaly, hepatomegaly and lymphadenopathy (there are exceptions to every rule). In some cases, very low numbers or no circulating blasts may be observed in peripheral blood smears. These latter patients are usually bi- or pancytopenic and bone marrow aspiration is required to identify the underlying cause for the cytopenias. This is typically the case in horses, where most animals with acute leukemia present with pancytopenia and low numbers to no circulating blasts. The diagnosis of acute leukemia requires the identification of more than 20-25% blasts in the bone marrow, i.e. a bone marrow aspirate is essential to confirm the diagnosis. A cut-off of 20% blasts is used for the diagnosis of AML with a cut-off of 25% used to distinguish ALL from lymphoma (Swerdlow et al 2008). However, by the time we see most veterinary patients, blasts dominate in marrow comprising >70-80% of marrow cells. AML in a dog (bone marrow) AML in a dog (venous blood) Acute leukemias can be of myeloid or lymphoid lineage, although there are undifferentiated or mixed phenotype leukemias (demonstrating markers of lymphoid and myeloid lineage). In our experience (Stokol et al 2015) and some published studies (Vernau and Moore, 1999), most acute leukemias are myeloid in origin in dogs. Horses can suffer equally from acute lymphoid or myeloid leukemia (Barrett et al 2017). AML is also more common in the cat and was, in many cats, caused by Feline Leukemia virus (FeLV) until the advent of FeLV vaccination which markedly decreased the frequency of these leukemias. T cell acute leukemia (which is very difficult to distinguish from lymphoma, which has heavily infiltrated the marrow and numerous tumor cells are in blood) is the next most common type we see at Cornell University, with rare B cell acute leukemias. Unlike humans, AML can occur in dogs of any age and we frequently see it in very young dogs (this seems particularly true of the T-ALL/lymphoma). Although a diagnosis of acute leukemia can be made from blood and bone marrow aspirate smears, differentiation of AML from ALL requires more than morphologic assessment of blasts (all blasts can look alike). Cytochemistry and immunophenotyping (but not clonal gene rearrangements) are required for classification of acute leukemia – ALL from AML and the different types of AML. This may be very important as ALL may be more responsive to aggressive chemotherapy and are treated with different chemotherapeutic agents (typically a lymphoma protocol) than AML. In individual cases it can be difficult to determine the type of acute leukemia. This is because neoplasms frequently display aberrant marker expression or lineage infidelity. For example, in our experience, many cases of AML can express T cell markers (CD3, weak CD5) and rarely B cell markers (CD22) (Stokol et al 2015). The expression of T cell markers in AML (especially monoblastic variants) make sense with new information being gleaned on hematopoiesis from murine models. These models posit that erythroid and megakaryocytic cells branch off before lymphoid and myeloid progenitors and that there is common lymphoid-myeloid progenitor. Indeed, B cells also appear to split off earlier from this common lymphoid-myeloid progenitor, with T cells and monocytes (in particular) staying together longer before differentiating down their specific lineages (Kawamoto et al 2010, Görgens et al 2013). In cases of acute leukemia, all available tools at our disposal (multiple markers, immunophenotyping and cytochemical staining) should be applied to determine lineage and clearly differentiate ALL from AML. In individual cases, the diagnosis is still difficult and then it comes down to preponderance of evidence – is the leukemia demonstrating more myeloid than lymphoid markers (then it is likely an AML) or lymphoid than myeloid markers (then it is likely an ALL). Most reports of acute leukemia in dogs have differentiated ALL from AML based on very limited marker expression and it is likely that many of these leukemias were misclassified. Lymphoid leukemia in a dog Acute lymphoid/lymphoblastic leukemiaAcute lymphoid/lymphoblastic leukemia is generally sub-classified by phenotype as T-ALL, B-ALL or NK-ALL (natural killer cell). The neoplastic cells are not invariably large. We have seen small, intermediate, and large cell variants of ALL. The WHO recently updated their classification scheme of lymphoid neoplasms (Swerdlow et al 2008).
The precursor lymphoid neoplasm spectrum Once a leukemia has been designated as lymphoid, the biggest decision to make is: Is it an immature (precursor) lymphoma from an extramedullary site infiltrating the bone marrow or circulating in blood (leukemic phase of lymphoma) or is it an ALL arising in the bone marrow? This distinction can be difficult to make and we use various bits of information gleaned from the animal (see more below). The difficulty in distinguishing lymphoid leukemia from lymphoma not only applies to immature or precursor cell lymphoid neoplasms, but also to the mature or chronic lymphoid neoplasms, i.e. mature forms of lymphoma and chronic lymphocytic leukemia (CLL). Indeed, sometimes we call these tumors lymphoma/leukemia when the distinction cannot be made with confidence. Ultimately, the differentiation of lymphoid leukemia (acute or chronic) from lymphoma (immature or mature) boils down to one question: Which is the main site of involvement? Bone marrow (for ALL), blood (for CLL) or extramedullary tissues (for lymphoma). The lymphoid neoplasms should be considered spectrums of one disease. For precursor cell neoplasms, at one end of the spectrum you have primary bone marrow involvement which dominates the clinical picture or an ALL. On the other end of the spectrum, you have a picture dominated by peripheral lymphoid tissue involvement (lymph nodes, liver, spleen), i.e. immature/lymphoblastic lymphoma. And then you have everything in between, where there is overlap between these two extremes. The animals showing overlap are the most difficult to definitively characterize. Acute myeloid leukemiaAcute megakaryoblastic leukemia in a dog Acute myeloid leukemia in animals fit into the World Health Organization classification of AML-NOS (not otherwise specified), which are generally sub-classified according to the old French-American-British (FAB) criteria (Swerdlow et al 2008, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition). The FAB criteria depends on morphologic features of differentiation and expression of differentiation markers by the tumor cells. In our experience, AML-NOS, acute monoblastic/mononocytic leukemia (AML-M5) is the most common subtype of AML in the dog (Stokol et al 2015, Stokol et al 2017) and acute erythroid leukemia (AML-M6) is the most common subtype seen in the cat (Blue et al 1988, Jain et al 1991), although the latter is infrequently seen nowadays since the advent of FeLV vaccination. With the advent of epigenetics and genetic testing, the classification scheme for myeloid leukemias has been recently revised and will continue to be a work in progress (Arber et al 2016). More details on AML are provided on this page. Chronic leukemiaPresumptive essential thrombocythemia with basophilia in a dog Chronic leukemias are characterized by the expansion of differentiated cells in the blood. Chronic leukemia can be lymphoid or myeloid in origin. The term “chronic” applies to the stage of maturation of the tumor, i.e. differentiated or mature. However, chronic also yields information on onset and progression. Chronic leukemia, unlike acute leukemia, usually has a protracted clinical course and these neoplasms are often diagnosed as an incidental finding in animals presenting for other complaints. Most importantly, all chronic myeloproliferative diseases (chronic myeloid leukemia) are exceedingly rare in animals. Most causes of very high leukocyte (non-lymphoid), platelet and red blood cell counts are not due to chronic myeloid leukemia but cytokine-driven or reactive extramedullary causes of bone marrow hyperplasia, e.g. paraneoplastic leukocytosis secondary to various carcinomas is more likely than a chronic neutrophilic leukemia (Dole et al 2004, Benson et al 2015), erythrocytosis secondary to hypoxia, renal disease or underlying neoplasia is more likely than a polycythemia vera (Moore and Stepien 2001, Axon et al 2008, Durno et al 2011). Bone marrow aspiration is generally not useful for diagnosis of chronic myeloid leukemias because the marrow shows hyperplasia of the affected cell lines in either neoplastic or non-neoplastic mature cell expansions, i.e. a myeloid hyperplasia is observed in both CGL and a leukocytosis that is cytokine-driven from a neoplasm. Similarly, a diagnosis of CLL should be reserved for those patients in which a cause for the lymphocytosis (e.g. reactive antigenic stimulation, epinephrine response, thymoma) is not found (Avery and Avery 2007). Immunophenotyping and clonality can also help confirm a diagnosis of CLL, but is not without caveats (see below). Just like chronic myeloid leukemias, a bone marrow aspirate may not be useful for diagnosis of CLL as the marrow is not always infiltrated (it is not the primary site of origin). Chronic lymphocytic leukemia is also uncommon in animals. For all types of chronic leukemia, a presumptive diagnosis can be made if there is an unexplained persistent (and generally increasing) leukocytosis documented on multiple occasions (over several months). An intensive diagnostic investigation should be undertaken in such animals to rule out occult neoplasia or abscesses which may be driving the expanded cell numbers. In our experience, the most common chronic leukemia is CLL. This is also the most common cause of a persistent lymphocytosis in dogs. Chronic lymphocytic leukemiaChronic lymphocytic leukemia is considered a neoplasm of accumulation, i.e. the genetic mutation prevents cell death, resulting in accumulation of the mature differentiated cells. There are three different general types of CLL:
The mature lymphoid neoplasm spectrum Since the mature lymphoid leukemias (CLL) appear to arise in extramedullary sites, they do not always involve the bone marrow so bone marrow is not always helpful for diagnosing CLL. Even though they arise in lymphoid organs, the main site of involvement is blood, helping distinguish the mature chronic lymphocytic leukemias from mature lymphomas (e.g. small cell lymphoma). Similar to immature cell lymphoid neoplasms, mature lymphoid tumors comprise a spectrum of likely one disease. At one end of the spectrum you have primary blood involvement which dominates the clinical picture or a CLL. On the other end of the spectrum, you have a picture dominated by peripheral lymphoid tissue involvement (lymph nodes, intestinal tract), i.e. small cell lymphoma. And then you have everything in between, where there is overlap between these two extremes. The animals showing overlap are the most difficult to definitively characterize.(see more below and spectrum image). A lymphocytosis could be due to reactive antigenic stimulation (e.g. an expected finding in young dogs, cats and horses, Ehrlichia canis infection in dogs), other tumors (e.g. thymoma, uncommon), epinephrine response (cats, common, should be transient), and hypoadrenocorticism in dogs (uncommon). Clonality assessment can help distinguish between non-neoplastic and neoplastic causes of lymphocytosis, but clonal expansions of T and B cells have been documented in dogs with Ehrlichia canis and Borrelia burgdorferi infection, respectively (Avery and Avery 2007) so infectious disease testing should be done in all animals with a persistent lymphocytosis that is not explainable. Immunophenotyping can also help…expanded numbers of a single type of lymphocyte (e.g. CD4 helper cells) or aberrant expression patterns (e.g. decreased expression of MHCII) can help distinguish neoplastic from non-neoplastic lymphocytosis. Chronic leukemia of granular lymphocytes Again, some infectious agents, notable Ehrlichia canis, can cause a clonal expansion of CD8+ T cells, which may have granules in their cytoplasm (Heeb et al 2003). So clonality or a uniform phenotype does not always equal cancer. Chronic myeloid leukemiaWith chronic myeloid leukemia, the genetic mutation causes proliferation and differentiation, so these diseases are characterized by high counts of the involved cell lineage, in peripheral blood. Chronic myeloid leukemias fit under the WHO designation of chronic myeloproliferative disorders, of which there are several sub-types as indicated below (Arber et al 2016). The term “chronic myeloid leukemia” can be confusing as it is used to describe the umbrella term for these various sub-types (although in reality, the term chronic myeloproliferative disorder should be used instead), as well as a specific subtype, which is characterized by the “Philadelphia chromosome” or a translocation between the genes bcl (chromosome 22) and abr (chromosome 9) which results in constitutive cell proliferation secondary to a tyrosine kinase. A similar translocation has been identified in dogs and is called the “Raleigh” chromosome (Breen and Modiano 2008). As for CLL, any expansion in leukocytes (non-lymphoid), platelets or red blood cells must be distinguished from cytokine-driven or reactive responses. Chronic myeloproliferative neoplasms are quite rare in animals and a cytokine-driven response should be considered the main differential diagnosis for increases in hematopoietic lineages before a chronic myeloid leukemia. Cytokine stimulation (either due to inflammation or secondary to cancer) is the most common cause of an unexplained neutrophilia or monocytosis in an animal. The following are sub-types of chronic myeloproliferative disorders:
There are other types of chronic myeloproliferative disorders that also show features of abnormal maturation or myelodysplasia. These are categorized as a separate group of neoplasms (myelodysplastic/myeloproliferative or MDS/MPD) and include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (negative for Philadelphia chromosome [Marino et al 2017]), MDS/MPD with sideroblasts and thrombocytosis, and juvenile myelomonocytic leukemia (Arber et al 2016). There has also been a report of dendritic cell leukemia in a dog (Allison et al., 2008). LymphomaLymphoma in a dog’s lymph node This is a neoplastic proliferation of lymphoid cells (excluding plasma cells) that arises in extramedullary tissue. Lymphoma cells can, but do not always (by morphologic criteria) infiltrate the marrow secondarily (called stage V disease). The bone marrow infiltrates are often seen amongst a normal hematopoietic population and range from patchy to diffuse. In most affected animals, particularly B cell lymphomas, the tumor cells comprise <25% of cells in marrow. Some patients with lymphoma can also have circulating lymphoma cells (with or without bone marrow involvement), which has various terms, including leukemic phase of lymphoma (used at Cornell University), lymphoma with circulating cells, lymphoma-associated leukemia, lymphoma with secondary leukemia (and is also classified as stage V disease). A lymphoma with a leukemic phase is more commonly seen in dogs than cats, but does occur in cats with thymic, hepatic, and splenic lymphoma. Also, animals can have marrow infiltrates without detectable circulating lymphoma cells (e.g. spinal lymphomas in cats). Lymphoma cells in blood or bone marrow will resemble the primary tumor, i.e. will be blasts if the primary tumor is a large cell lymphoma or intermediate cells from an intermediate cell lymphoma. Blasts from large cell lymphomas are easier to identify in peripheral blood than lymphoma cells from intermediate or small lymphomas. This is because blasts are not normally seen in blood, whereas normal blood lymphocytes consist of small, with fewer intermediate, cells. The number of circulating lymphoma cells varies from very low (i.e., not included in the differential cell count) to very high. When there are large numbers of lymphoid cells in blood or bone marrow (>25% or diffuse infiltrates), it can be very difficult to distinguish between lymphoma and leukemia, i.e. a lymphocytosis consisting of small lymphocytes could be a small cell lymphoma with a leukemic phase or a CLL; a lymphocytosis of larger cells could be a large cell lymphoma with a leukemic phase or an acute leukemia (do not assume it is lymphoid until phenotyping is done). Lymphoma or leukemia?CLL or small cell lymphoma in a cat A large cell lymphoma with a leukemic phase can mimic an acute leukemia (myeloid or lymphoid), which is characterized by variable numbers of blasts in circulation. Alternatively, a small to intermediate cell lymphoma with a leukemic phase can resemble a CLL or an ALL (which can consist of small to intermediate cells usually with fine chromatin, versus AML which usually consists of blasts). We use the following to distinguish between a lymphoma with a leukemic phase and an acute leukemia (which arises primarily in the bone marrow) before we know the true phenotype of the cells (see also the algorithm above):
Myelodysplastic syndromesMyelodysplastic syndromes (MDS) are a group of clonal hematologic disorders that share the general characteristics of ineffective hematopoiesis and abnormal maturation in more that one cell line. Because MDS can progress to acute myeloid leukemia (AML), they have been called preleukemia. Subgroups of MDS are defined by specific criteria but, in general, typical hematologic findings are cytopenias in peripheral blood with normo- to hypercellular marrow, a fairly heterogeneous mixture of hematopoietic cells in marrow, and morphologic evidence of abnormal maturation. In the erythroid series, morphologic abnormalities include asynchronous maturation of nucleus and cytoplasm, megaloblastic cells, and siderotic granules. Atypia in megakaryocytes includes very small (about the size of a neutrophil) mononuclear and multinuclear megakaryocytes and larger megakaryocytes with lumpy round nuclei or nuclei with bizarre lobulation. In the granulocyte lines, abnormalities include hyposegmentation, hypersegmentation,abnormal granules, and an increase in immature cells. In some forms of MDS, the percentage of myelo- and/or monoblasts is increased (>5% but < 30%). Identifying the morphologic evidence of dysplastic maturation is important to distinguish neoplastic ineffective hematopoiesis from that caused by immune mechanisms. A classification system developed for human patients by the French-American-British (FAB) cooperative group is applicable, with modifications, to veterinary patients. The natural progression of MDS is variable. The outcome may be death due to lack of mature blood cells (severe anemia, thrombocytopenia, neutropenia), stable disease and death due to unrelated causes, or progression to acute myeloid leukemia and infiltration of extramedullary tissue by non-lymphoid blasts. At present, there is no effective therapy for MDS in animals but supportive treatment, especially transfusions, can prolong survival and maintain quality of life. Which type of leukemia is characterized by the proliferation?Chronic lymphocytic leukemia is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. It is the most common adult leukemia in Western populations and comprises 25 to 30 percent of leukemias in the United States.
What is Type T leukemia?T-cell prolymphocytic leukemia (T-PLL) is an extremely rare and typically aggressive malignancy (cancer) that is characterized by the out of control growth of mature T-cells (T-lymphocytes). T-cells are a type of white blood cell that protects the body from infections.
What is an immature lymphocyte called?About lymphocytes
In people with ALL, new lymphocytes do not develop into mature cells, but stay as immature cells called lymphoblasts.
Is characterized by the proliferation of immature leukocytes?Leukemia is a neoplastic disease characterized by an excessive proliferation of immature white blood cells and their precursors.
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