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Myeloproliferative Disorders Kristin L. Henson | Rose E. Raskin
MYELODYSPLASTIC DISORDERS Deﬁnition and Classiﬁcation
C. Dysplastic changes involving platelets include giantism, hypergranularity, or hypogranularity. D. Dwarf or micromegakaryocytes with asynchrony of maturity are common signs of dysthrombopoiesis. III. Despite the altered development of these precursors (from increased apoptosis), the bone marrow is generally hypercellular, with blast forms accounting for <30% of nucleated cells. IV. Myeloﬁbrosis is often present in the marrow of cats with MDS (Blue, 1988). V. Feline leukemia virus infection is common in cats with MDS (Hisasue et al., 2001)
I. Primary myelodysplastic syndrome (MDS) consists of irreversible, acquired clonal (neoplastic) disorders of multipotential hematopoietic cells unrelated to concurrent diseases, nutritional deﬁciency, or drug-induced toxicosis. II. Animals with MDS (“preleukemia”) often suffer from chronic debilitation that may continue unchanged or evolve into acute myeloid leukemia (AML). III. Myelodysplastic disorders are morphologically divided into subtypes (Table 66-1) relative to the percentage of myeloblasts in the bone marrow and the myeloid-to-erythroid (M:E) ratio. A. MDS-refractory cytopenia (MDS-RC) and MDS-excess blasts (MDS-EB) have an M:E ratio >1.0. B. The subtype MDS-erythroid predominance (MDS-Er) refers to feline cases with an M:E ratio ≤1.0 (Raskin, 1996; Jain et al., 1991), but has also been considered a variant of MDS-RC in dogs (Weiss, 2005). IV. MDS-EB may be considered a form of oligoblastic leukemia that often behaves as an antecedent of AML and has a worse prognosis (McManus and Hess, 1998; Weiss, 2005).
Treatment and Monitoring
I. II. III. IV.
Chronic infections with fever Lethargy related to anemia Anorexia Hemorrhage
Diagnosis I. The peripheral blood indicates cytopenia of one or more cell lines, with ineffective hematopoiesis. II. Abnormal morphology (dyshematopoiesis) must be observed in either the erythroid, granulocytic, or megakaryocytic cells. A. Dysplasia in the erythroid line may involve macrocytosis, megaloblastosis with asynchrony of maturation, nuclear fragmentation, unequal cell division, sideroblastosis, or siderocytosis. B. The granulocytic line may exhibit giant forms, nuclear hypersegmentation, hyposegmentation, or abnormal cytoplasmic granulation as evidence of dysmyelopoiesis. 656
I. The main differential diagnosis is secondary MDS, which includes cobalamin or folate deﬁciencies, drug-induced toxicosis, or concurrent immune-mediated or neoplastic diseases. II. Other myeloid neoplasms, such as chronic granulocytic leukemia (CGL), chronic myelomonocytic leukemia (CMMoL), and chronic monocytic leukemia (CMoL), have <30% blast cells in the bone marrow and may have dyshematopoiesis.
I. Because the condition may persist for long periods without signiﬁcant clinical disease, the goal of treatment is often supportive, with antibiotics and blood transfusions. II. A few cases have been treated, but with limited success. A. Dogs: human recombinant erythropoietin at 100 U/kg SC QOD for 10 days and prednisone at 2 mg/kg PO SID initially (Boone et al., 1998) B. Dogs: low doses of aclarubicin at 5 mg/m2 IV SID for 5 days (Miyamoto et al., 1999) C. Cats 1. Several treatment protocols were used for 16 cats (Hisasue et al., 2001). 2. Whole blood transfusion was used to improve clinical signs in 15 cats. 3. Prednisolone 1 to 4 mg/kg PO, IM SID was used in combination with other drugs for 13 cats. 4. Low-dose cytarabine 0.7 to 1.4 mg/kg SC SID or cytarabine ocfosfate 2 to 4 mg/kg PO SID for 2 to 4 weeks was used along with prednisolone in nine cats.
TA BL E
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Myeloproliferative Disorders TYPES AND SUBTYPES
Myeloblasts <30% of ANC; peripheral cytopenias and dyshematopoiesis common; may evolve into acute myeloproliferative disorder M:E ratio ≤1, myeloblasts <5% of ANC M:E ratio >1, myeloblasts <5% of ANC M:E ratio >1, myeloblasts ≥5% of ANC Requires electron microscopy and/or immunophenotyping Blast cells ≥30% of ANC
MDS-Er (cats) MDS-RC (cats/dogs) MDS-EB (cats/dogs) Acute undifferentiated leukemia Acute myeloid leukemia* Acute myeloblastic leukemia Without maturation With maturation Acute myelomonocytic leukemia Acute monocytic leukemia Without maturation With maturation Acute erythroleukemia With erythroid predominance Acute megakaryoblastic leukemia Chronic myeloproliferative diseases Chronic granulocytic leukemia Eosinophilic leukemia Basophilic leukemia Chronic myelomonocytic leukemia Chronic monocytic leukemia Polycythemia vera Essential (primary) thrombocythemia Chronic idiopathic myeloﬁbrosis Related myeloproliferative disorders Malignant histiocytosis Mast cell leukemia
Type I myeloblasts ≥90% of ANC Types I-II myeloblasts ≥30% and ≤90% of ANC; also granulocytes ≥10% and monocytes ≤20% of NEC Myeloblasts and monoblasts ≥30% of ANC; also of differentiated granulocytes and monocytes ≥20% of NEC each Monoblasts and promonocytes ≥80% of NEC Promonocytes and monocytes ≥30% to ≤80% of NEC Erythroid cells >50% of ANC (M:E <1), myeloblasts and monoblasts ≥30% of NEC Erythroid cells >50% of ANC, rubriblasts, myeloblasts, and monoblasts ≥30% of ANC Megakaryoblasts >30% of ANC Myeloblasts <30% of ANC; also mild to moderate hematodysplasia; may evolve into acute myeloproliferative disorder Marked neutrophilia Marked eosinophilia Marked basophilia Persistent monocytosis Persistent monocytosis Erythropoietin-independent erythrocytosis Thrombopoietin-independent thrombocytosis Anemia with leukoerythroblastosis, extramedullary hematopoiesis, splenomegaly, and marrow ﬁbrosis Derived from hematopoietic stem cell Cytopenia and erythrophagia are common; pleomorphic histiocytes with multinucleated giant cells Multiple cell lines affected; pleomorphic mast cells in size and nuclear features; erythrophagia possible
MDS, Myelodysplastic syndrome; ANC, all nucleated cells in bone marrow, excluding lymphocytes, plasma cells, macrophages, and mast cells; M:E, myeloid-to-erythroid; NEC, nonerythroid cells (ANC minus erythroid). *Classification of canine and feline acute myeloid leukemia by blast cell type and percentage based upon modification of FAB system by the Animal Leukemia Study Group (Jain NC, Blue JT, Grindem CB et al: Proposed criteria for classification of acute myeloid leukemia in dogs and cats. Vet Clin Pathol 20:63, 1991).
5. Cyclosporin A at 2.5 to 5 mg/kg PO SID with prednisolone was used in one cat. 6. Daunorubicin 20 mg/m2 IV SID for 3 days in 3 weeks, cytarabine at 100mg/m2 SC SID for 4 days in 3 weeks, vincristine at 0.025 mg/kg IV weekly, and prednisolone were tried in three cats with advanced disease. III. Animals with >5% marrow myeloblasts have shorter survival times and poorer responses to treatment (Couto and Kallet, 1984; Hisasue et al, 2001; Weiss and Smith, 2000).
ACUTE MYELOID LEUKEMIAS Deﬁnition and Classiﬁcation I. AMLs are malignant, clonal proliferations of immature nonlymphoid hematopoietic cells resulting in the accumulation of blast cells in the bone marrow, peripheral blood, visceral organs, and lymph nodes. II. Aleukemic, subleukemic, or occult leukemias are terms for acute leukemias in which blast cells are not observed, or are observed in low numbers in the peripheral blood, respectively.
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III. AML is subclassiﬁed in animals according to the hematopoietic lineage of the blast cell population. IV. In humans, AMLs have recently been reclassiﬁed under the World Health Organization (WHO) according to speciﬁc genetic abnormalities, therapy-related leukemias, presence of multilineage dysplasia, or leukemias with no evidence of genetic mutations, history of therapy, or dysplasia (Harris et al., 1999). V. Under the WHO classiﬁcation system, blast cell percentage for the diagnosis of acute leukemia decreased from 30% to 20% and use of the French-American-British (FAB) alphanumeric system (AML: M1-M7) has been discarded (Harris et al., 1999; Vardiman et al., 2002). VI. Classiﬁcation of AML is based on the Animal Leukemia Study Group report, which standardized the diagnosis of AML for evaluation of clinical prognosis and treatment in dogs and cats (Jain et al., 1991). A. Cytomorphology by light microscopy, cytochemical staining, and immunophenotyping are used to identify the lineage of blast cells for subclassiﬁcation of AML. B. The human WHO classiﬁcation system has not yet been evaluated in animals; however, in recognition of this new system, the AML: M1-M7 numbering system is not used in this chapter. C. Subtypes of canine and feline AML described by the Animal Leukemia Study Group are as follows (see Table 66-1): 1. Acute undifferentiated leukemia: lack morphological and cytochemical evidence of lineage for either lymphoid or myeloid cell types 2. Acute myeloblastic leukemia without maturation 3. Acute myeloblastic leukemia with maturation 4. Acute promyelocytic leukemia (not identiﬁed in animals) 5. Acute myelomonocytic leukemia 6. Acute monocytic leukemia a. Acute monocytic leukemia without maturation b. Acute monocytic leukemia with maturation 7. Acute erythroleukemia and/or acute erythroleukemia with erythroid predominance 8. Acute megakaryoblastic leukemia
Diagnosis I. Animals typically exhibit an acute onset and rapid progression of clinical signs related to peripheral blood abnormalities and organ or lymph node inﬁltration by leukemic cells. II. Hematological ﬁndings include either leukopenia or leukocytosis with a disorderly left shift, nonregenerative anemia with or without macrocytosis and nucleated red blood cells (normoblastemia), and thrombocytopenia. A. Circulating blast cells may or may not be present. B. A signiﬁcant monocytosis is usually present in acute monocytic leukemia. C. Morphological abnormalities in both marrow and circulating cells may include giant forms, granulocyte hypersegmentation, erythroid nuclear fragmentation
and abnormal cell division, asynchronous maturation of erythroid cells, and hypogranular platelets. Speciﬁc serum biochemical abnormalities suggest organ inﬁltration by neoplastic cells. Blast cells are sometimes seen in peripheral blood, lymph nodes, liver, spleen, occasionally kidneys, and cerebrospinal ﬂuid. Blast cells have round to indented nuclei, prominent single to multiple nucleoli, a high nuclear-to-cytoplasmic ratio, and basophilic cytoplasm. Deﬁnitive diagnosis requires identiﬁcation of blast cell lineage and their percentages in bone marrow, blood, or both using morphological examination, cytochemical staining, and immunophenotyping. A. Cytochemical stains are species speciﬁc (Raskin and Valenciano, 2000). B. Submission of samples to a veterinary reference laboratory for cytochemical staining and interpretation by a board-certiﬁed clinical pathologist is recommended. C. Cytochemical staining is most useful for identiﬁcation of myeloid, monocytic, and megakaryocytic neoplasms; good lymphocytic and erythroid cytochemical markers are lacking. D. Immunophenotyping (immunocytochemistry, immunohistochemistry, and ﬂow cytometry) using antibodies that recognize speciﬁc enzymes or structural epitopes on the leukemic cells is also used to differentiate AML and acute lymphoid leukemia (ALL) and to subclassify AML. E. Other diagnostic tests used to identify or conﬁrm blast cell lineage include ultrastructural analysis by electron microscopy and in vitro blast cell differentiation (Modiano et al., 1998). F. Use of a diagnostic algorithm derived from ﬂow cytometry light scatter patterns (without use of monoclonal antibodies) to provide a preliminary classiﬁcation of acute leukemia has also been evaluated and may provide more rapid evaluation of leukemias, although reﬁnement of the algorithmic process is still needed (Fernandes et al, 2002). G. Genetic studies in animal leukemias have detected chromosomal abnormalities, although more information is needed regarding karyotypic, molecular DNA abnormalities, and their association with therapy and prognosis.
Differential Diagnosis I. The primary and most signiﬁcant differential diagnosis of AML is ALL. II. In dogs and cats, lymphoid leukemia has a better response to chemotherapy and prognosis compared with AML; therefore, accurate differentiation is crucial. III. Although morphological criteria can be used for differentiation, cytochemical staining, immunophenotyping, or both are recommended to distinguish between AML and ALL.
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Chronic Granulocytic Leukemia
IV. Bone marrow aspirates usually reveal a hypercellular marrow with a moderate to markedly increased M:E ratio; increased numbers of promyelocytes, neutrophilic myelocytes, and myeloblasts; but the latter cells are <30% of all nucleated cells. A. Bone marrow interpretation is often that of a leukemoid response. B. Bone marrow histopathologic examination is recommended to monitor the degree of ﬁbrosis that may occur in later stages of CGL. V. Although inﬁltration of liver, spleen, and other organs by leukemic cells is common, serum biochemical proﬁles are generally normal to mildly altered. VI. Pseudohypoglycemia may occur from increased in vitro utilization of glucose by the excessive numbers of circulating granulocytes. VII. Aspirates or biopsy of lymph nodes and visceral organs often reveal granulocytic inﬁltration and extramedullary hematopoiesis. VIII. Rarely, a solid tumor of leukemic granulocytes (chloroma) is found.
Deﬁnition and Classiﬁcation
I. AML has an extremely poor prognosis, with survival times ranging from days to <3 months in treated animals. II. Supportive therapy is administered as needed. III. Chemotherapy for AML, if attempted, is instituted as soon as possible after deﬁnitive diagnosis because of the rapid clinical course. A. Various combinations of cytotoxic agents, including doxorubicin, cyclophosphamide, vincristine, cytosine arabinoside, 6-thioguanine, busulfan, melphalan, and prednisone, have been used. B. Common side effects of these agents include leukopenia and thrombocytopenia resulting from myelosuppression, and gastrointestinal (GI) toxicity resulting in vomiting, anorexia, and diarrhea (see Chapter 72).
CHRONIC MYELOPROLIFERATIVE DISEASES
I. In animals, chronic granulocytic leukemia (CGL) and chronic myelogenous leukemia (CML) are synonymous and refer to a form of chronic myeloproliferative disease (MPD) characterized by a neoplastic proliferation within the granulocytic (neutrophilic) cell line. II. CGL may terminate in a “blast crisis” with proliferation of immature blast cells and development of acute leukemia. III. In humans, CML is characterized by a speciﬁc genetic translocation to form the BCR-ABL fusion gene or Philadelphia chromosome within pluripotential stem cells resulting in proliferations of neutrophils as well as other leukocytes, and to which targeted gene therapy is now available (Vardiman et al, 2002). A. A true clonal proliferation of neutrophils (chronic neutrophilic leukemia) is considered rare in people. B. Similar genetic abnormalities, as identiﬁed in human CML, have not been identiﬁed in animals.
Diagnosis I. CGL is rare in animals; however, an increased risk has been reported in dogs exposed to high doses of radiation (Dungworth et al., 1969). II. The hallmark of CGL is a marked and persistent leukocytosis consisting primarily of bands and segmented neutrophils, although a disorderly left shift may be present. A. White blood cell (WBC) counts may range to >100,000 cells/mL. B. Abnormal morphological features or dysplasia, such as giant bands, hypersegmentation, pyknosis, and nuclear fragmentation, are absent or uncommon. III. Other laboratory ﬁndings are variable and include nonregenerative anemia ± normoblastemia, monocytosis, eosinophilia, basophilia, thrombocytopenia, and thrombocytosis.
I. The primary differential diagnosis for CGL is a leukemoid reaction (see Chapter 65) related to inﬂammation and manifested by marked neutrophilia with a left shift back to early precursors (progranulocyte or later). II. Conditions associated with leukemoid reactions include pyogenic infections; immune-mediated hemolytic anemia; and neoplasms associated with necrosis, sepsis, production of hematopoietic growth factors (paraneoplastic neutrophilia), or metastasis to the bone marrow. III. Exclusion of inﬂammatory diseases through appropriate clinical and diagnostic testing is used to rule out a leukemoid reaction and conﬁrm suspected CGL. IV. Laboratory criteria useful in the differentiation of CGL include the following (Fine and Tvedten, 1999): A. Persistent leukocytosis and left shift without evidence of neutrophil toxicity B. Macrocytic anemia accompanied by normoblastemia without a reticulocytosis C. Cytological evidence of granulocytopoiesis in lymph nodes and organs D. Histopathologic ﬁndings of granulocytic perivascular inﬁltration in liver, spleen, and other organs
Treatment I. Treatment is somewhat controversial, because untreated animals may survive weeks to years, and the success of chemotherapy in prevention of a terminal blast crisis is uncertain. II. Survival times of years can occur in treated animals, and reduction in numbers of circulating blasts via chemotherapy may decrease clinical signs and improve quality of life. A. Protocol 1: hydroxyurea 20 to 25 mg/kg PO BID until the WBC count decreases to 15,000 to 20,000 cells/mL,
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then tapered to 10 to 12 mg/kg PO SID or to 50 mg/kg PO every 3 to 4 days (Young and MacEwen, 1996) B. Protocol 2: hydroxyurea 50 mg/kg PO SID for 14 days until the WBC count is within normal reference range, then tapered to QOD and then to every 3 days (Leifer et al., 1983; Fine and Tvedten, 1999) C. Side effects of hydroxyurea: myelosuppression (most serious), pruritus, erythema, alopecia, hyperglycemia D. Protocol 3: busulfan 0.1 mg/kg/day PO until the leukocyte count is reduced to 15,000 to 20,000 cells/mL (Young and MacEwen, 1996) III. No successful chemotherapeutic treatment for CGL in a blast crisis has been reported. Eosinophilic Leukemia
Deﬁnition I. Eosinophilic leukemia (EL) is a rare chronic MPD occurring primarily in cats and is characterized by peripheral eosinophilia, eosinophilic hyperplasia of the bone marrow, and eosinophilic inﬁltration in multiple organs. II. EL is difﬁcult to distinguish from the more common hypereosinophilic syndrome (HES), and some controversy exists whether EL is a distinct clinical entity or a variant of HES. III. Support for the distinct, neoplastic nature of EL includes a more rapid disease progression, the presence of morphologically abnormal eosinophils, increased numbers of circulating and marrow eosinophilic precursors, and a more severe anemia (Huibregtse and Turner, 1994). IV. In humans, demonstration of clonality is used to distinguish EL from the polyclonal proliferation of HES (McManus, 2005), but no such clonality studies have been performed in animals with eosinophilic proliferations.
Clinical Signs and Diagnosis I. Older cats tend to be at greatest risk for EL, with a median age of 8 years at diagnosis. II. EL has been reported in feline leukemia virus/feline immunodeﬁciency virus-infected and noninfected cats. III. Affected animals may have vomiting, diarrhea, hepatosplenomegaly, and peripheral lymphadenopathy. IV. Common laboratory ﬁndings include peripheral eosinophilia, hypogranular and immature eosinophils, moderate to severe anemia, and thrombocytopenia. V. Bone marrow aspiration typically reveals eosinophilic hyperplasia with a signiﬁcantly increased M:E ratio (>10:1), increased numbers of immature eosinophils, and dysmyelopoiesis.
Differential Diagnosis I. Primary differential diagnoses for EL are HES and conditions associated with reactive eosinophilia, such as allergic bronchitis, pulmonary inﬁltrates with eosinophils, external and GI parasitism, heartworm disease, hypersensitivity reactions, eosinophilic enteritis, eosinophilic granuloma
complex, and neoplasia (mast cell tumor, lymphoma, certain carcinomas). II. Deﬁnitive diagnosis of EL requires a thorough clinical and diagnostic evaluation to rule out reactive eosinophilia and HES.
Treatment I. Response to treatment in cats with EL is generally poor. II. Average survival times of 6 months postdiagnosis have been reported with corticosteroid therapy (Goldman and Graham, 2000). III. Give hydroxyurea initially at 40 mg/kg/day PO for 1 week, then QOD or every 3 days as needed to control the eosinophilia and prevent the development of neutropenia (Hamilton, 2002). IV. Hydroxyurea is used in combination with prednisone 2 mg/kg PO BID initially, then reduced gradually. Basophilic Leukemia
Deﬁnition and Classiﬁcation I. Basophilic leukemia (BL) is a chronic MPD rarely reported in dogs or cats. II. BL is characterized by excessive marrow production of basophils, resulting in peripheral basophilia, increased circulating and marrow immature basophils, and increased numbers of marrow myeloid blast cells.
Clinical Signs and Diagnosis I. Clinical signs of BL are nonspeciﬁc and include lethargy, inappetence, fever, lumbar pain, hepatosplenomegaly, and lymphadenopathy. II. Clinicopathologic ﬁndings of basophilia, neutropenia, nonregenerative anemia, and thrombocytosis have been reported. III. Bone marrow ﬁndings in one reported case of BL included 43% basophils and 29% marrow blast cells of all nucleated cells, with some blast cells exhibiting dark, basophilic-like granules (Mears et al., 1997). IV. Cytochemical staining of marrow and blood smears with omega-exonuclease, a basophil-speciﬁc marker have been used to identify basophilic lineage of marrow blast cells and conﬁrm the presence of immature and mature basophils (Mears et al., 1997).
Differential Diagnosis I. BL must be differentiated from reactive basophilia associated with a hypersensitivity reaction, inﬂammation, or mast cell tumor/mastocytosis. II. BL can occasionally be confused with mast cell leukemia because of the presence of dark cytoplasmic granules in both cell types. A. Basophils have a segmented nucleus and variable numbers of dark purple cytoplasmic granules. B. Mast cells are generally larger than basophils and possess a round nucleus with many small, metachromatic-
staining granules that appear pink to purple with Romanowsky-type stains.
Treatment I. Give hydroxyurea at 20 to 25 mg/kg PO BID (Mears et al., 1997). II. Side effects, such as severe myelosuppression, pruritus, alopecia, and diabetes mellitus, may require discontinuation of hydroxyurea in dogs with BL (Mears et al., 1997). Chronic Myelomonocytic Leukemia/ Chronic Monocytic Leukemia
Deﬁnition and Classiﬁcation I. CMMoL and CMoL are clonal disorders with some similarity to CGL in that they present with increased granulocytic or monocytic counts, anemia, mild to moderate myelodysplasia, and <30% blast cells of all nucleated cells in the bone marrow. II. CMMoL may occur as a form of oligoblastic or subacute leukemia, especially in cats, and may progress to acute leukemia (Raskin and Krehbiel, 1985; Hisasue et al., 2001). III. In the human WHO classiﬁcation system, CMMoL is placed in the category of myelodysplastic/myeloproliferative disease, as the disease displays both neoplastic and dysplastic features (Vardiman et al., 2002). IV. In animals, CMMoL has been classiﬁed as a chronic myeloproliferative disorder (Jain et al., 1991) or a myelodysplastic disorder (Hisasue et al., 2000, Hisasue et al., 2001; Valli et al., 2002).
Clinical Signs and Diagnosis I. Characteristic features of CMMoL and CMoL include an indolent clinical course with a persistent monocytosis unresponsive to antibiotic therapy. II. Splenomegaly and hepatomegaly are common ﬁndings. III. Bone marrow aspirates in CMoL reveal increased numbers of monoblasts and other monocytic precursors, particularly after splenectomy. IV. The marrow contains >3% but <30% myeloblasts of all nucleated cells. V. Peripheral blood ﬁndings include monocyte counts usually >10% (or >1,000/mL), low numbers of immature granulocytes (≤10%), some blast cells (<2%), and the presence of prominent granulocytic dysplasia.
Differential Diagnosis I. Primary differential diagnoses for CMMoL and CMoL are inﬂammatory disorders, such as deep mycoses, immunemediated diseases, and CGL. II. Basophilia is common in CGL but not in CMMoL. III. Demonstration of a persistent and unresponsive monocytosis, cytological and histological evidence of neoplastic cell inﬁltration in lymph nodes and other organs, and elimination of inﬂammatory causes for the leukocytosis are necessary to differentiate between CMMoL or CMoL and inﬂammatory disorders (Bearman et al., 1981).
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Treatment Treatment using combination chemotherapy and glucocorticoids has been attempted, but has not changed the course of disease. Polycythemia Vera See Chapter 64. Essential (Primary) Thrombocythemia
Deﬁnition and Classiﬁcation I. Essential thrombocythemia (ET) is an uncommon MPD characterized by a proliferation of bone marrow megakaryocytes resulting in a signiﬁcant and persistent thrombocytosis (>600,000/mL). II. Evolution of ET to CGL has been reported in a dog (Degen et al., 1989).
Diagnosis I. Clinical signs of ET are nonspeciﬁc and include lethargy, exercise intolerance, pallor, and hepatosplenomegaly. II. Hemorrhage (GI or epistaxis) attributable to intrinsic platelet function defects may occur and contribute to anemia. III. Thrombotic events (pulmonary embolism) related to the increased platelet mass, platelet hyperaggregation, or both, can arise. IV. Splenectomy may unmask and exacerbate the disease (Degen et al., 1989). V. Laboratory ﬁndings include a persistent thrombocytosis that may exceed 1,000,000 platelets/mL; large and hypergranular platelets (shift platelets), elevated mean platelet volume, minimally regenerative or nonregenerative anemia, neutrophilia, basophilia, and eosinophilia. VI. Pseudohyperkalemia, most likely from release of intracellular potassium during clot formation, may be noted on the serum biochemical proﬁle. VII. Bone marrow aspiration reveals increased numbers of megakaryocytes, some of which may exhibit abnormal morphology, as well as erythroid hypoplasia, myeloid hyperplasia, sheets of large granular platelets, and increased numbers of free megakaryocyte nuclei. VIII. Bone marrow histopathology often reveals increased paratrabecular reticulin ﬁbrosis. IX. Increased numbers of splenic megakaryocytes in the absence of extramedullary hematopoiesis are suggestive of splenic inﬁltration by leukemic cells (Dunn et al., 1999).
Differential Diagnosis I. ET must be differentiated from conditions associated with reactive thrombocytosis, including iron deﬁciency, chronic blood loss anemia, chronic inﬂammation, solid tissue neoplasia, and other forms of MPD (see Chapter 67). II. In humans, the Polycythemia Vera Study Group recommends the following criteria for diagnosis of ET (Murphy et al., 1986): A. Platelet count >600,000 cells/mL, with platelet counts usually >1,000,000 cells/mL
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B. A normal initial hematocrit or packed-cell volume that does not increase with iron supplementation C. Normal serum iron concentration and presence of stainable iron in the bone marrow D. No evidence of collagen ﬁbrosis in bone marrow E. No identiﬁable cause for reactive thrombocytosis and no circulating blasts
Treatment I. Asymptomatic animals may not require treatment. II. In dogs, possible treatments include the following: A. Radiolabeled phosphorus in combination with melphalan (Degen et al., 1989) B. A combination protocol with cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (Simpson et al., 1990) C. Vincristine (0.7 mg/m2 once IV) and hydroxyurea (500 mg/m2 PO per day) (Favier et al., 2004). 1. The hydroxyurea dose was increased (2000 mg/m2 PO per day) after 3 weeks in both dogs owing to insufﬁcient response. 2. The dogs’ conditions deteriorated, however, and pancytopenia was noted in the bone marrow at necropsy, most likely from the high-dose hydroxyurea therapy. III. The following may be tried in cats: A. Nandrolone decanoate 15 mg IM once (Evans et al., 1982) B. Melphalan 0.5 mg PO SID for 4 days, then 0.5 mg PO QOD (Hammer et al., 1990) Chronic Idiopathic Myelofibrosis
Deﬁnition and Classiﬁcation I. Many synonyms, such as agnogenic (idiopathic) myeloid metaplasia, osteomyelosclerosis, and chronic megakaryocytic-granulocytic myelosis, apply to this neoplastic transformation of a single hematopoietic stem cell. II. The condition results in intramedullary and extramedullary hematopoiesis often accompanied by a nonclonal ﬁbroblastic reaction of the bone marrow. III. Myeloid metaplasia refers to those cases with neoplastic proliferation of predominately granulocytic and megakaryocytic precursors in organs, such as the spleen and liver, with or without marrow ﬁbrosis. IV. Primary myeloﬁbrosis involves the replacement of normal hematopoietic tissue with increased ﬁbroblasts depositing ﬁne reticulin and thick collagen ﬁbers (Breuer et al., 1999b). V. Some cases of agnogenic myeloid metaplasia or idiopathic myeloﬁbrosis were previously diagnosed as AMLM7 (Breuer et al., 1999a).
Clinical Signs and Diagnosis I. Clinical signs include a gradual onset of lethargy, exercise intolerance, inappetence, pale mucous membranes, vomiting, diarrhea, fever, weight loss, and splenomegaly (Weiss and Smith, 2002).
II. Characteristic features include circulating immature granulocytes and erythroid cells (leukoerythroblastic reaction), splenomegaly, hepatomegaly, extramedullary hematopoiesis, and myeloﬁbrosis. III. Clinicopathologic abnormalities include nonregenerative anemia, poikilocytosis, dacryocytosis (teardrop-shaped erythrocytes), leukocytosis or leukopenia, thrombocytosis or thrombocytopenia (in addition to a leukoerythroblastic reaction), and pancytopenia as the disease progresses. IV. Extramedullary hematopoiesis is often present in the spleen, liver, or both. V. Intramedullary megakaryocytopoiesis involving variably sized or polymorphic precursors is commonly found associated with argyrophilic reticulin ﬁbrosis. VI. Diagnosis of myeloﬁbrosis requires bone marrow histopathology to document replacement of normal marrow architecture by excessive amounts of collagen and reticulin ﬁbers. A. Evidence of marrow necrosis may be noted. B. Aspiration for cytological examination is often unrewarding (dry tap).
Differential Diagnosis I. The main differential diagnosis for primary myeloﬁbrosis is secondary myeloﬁbrosis associated with bone marrow damage and necrosis from conditions such as marrow neoplasia (lymphoproliferative, myeloproliferative, or metastatic), tumors outside the bone marrow, immunemediated hemolytic anemia, congenital hemolytic anemia (see Chapter 64), drug-induced marrow damage, ehrlichiosis (see Chapter 115), and irradiation. II. Other rule outs include CML, ET, and acute megakaryoblastic leukemia based on the neoplastic proliferation of granulocytic and megakaryocytic precursors.
Treatment and Monitoring I. Immune-mediated destruction of erythroid precursors has been hypothesized to be a factor in the development of myeloﬁbrosis in some dogs (Villiers and Dunn, 1999), so therapy is difﬁcult. II. Treatments that may be tried include the following (Villiers and Dunn, 1999): A. Blood transfusions B. Prednisolone 2 to 3 mg/kg PO SID for 3 to 4 weeks, then QOD with tapering of the dose as anemia resolves C. Nandrolone decanoate 2 mg/kg IM weekly for 3 weeks, then once every 3 weeks D. Azathioprine 2 mg/kg PO QOD if the anemia does not respond to initial treatments III. In one study, four of seven dogs responded with resolution of anemia and survived for more than 2 years without continued treatment (Villiers and Dunn, 1999).
RELATED MYELOPROLIFERATIVE DISORDERS Malignant Histiocytosis See Chapter 77.
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66 | Myeloproliferative Disorder
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9 | Hemolymphatic System
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