Myeloproliferative Disorders

Myeloproliferative Disorders

656 SECTION 9 | Hemolymphatic System CHAPTER 66 Myeloproliferative Disorders Kristin L. Henson | Rose E. Raskin MYELODYSPLASTIC DISORDERS Definit...

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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).

Differential Diagnosis

Clinical Signs

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.

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Myeloproliferative Disorders TYPES AND SUBTYPES

MORPHOLOGICAL CHARACTERISTICS

Myelodysplastic disorders

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

III. IV.

V.

VI.

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

Differential Diagnosis

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-

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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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Mast Cell Leukemia See Chapter 65. Bibliography Bass MC, Schultze AE: Essential thrombocythemia in a dog: case report and literature review. J Am Anim Hosp Assoc 34:197, 1998 Bearman RM, Kjeldsberg CR, Pangalis GA et al: Chronic monocytic leukemia in adults. Cancer 48:2239, 1981 Blue JT: Myelofibrosis in cats with myelodysplastic syndrome and acute myelogenous leukemia. Vet Pathol 25:154, 1988 Boone LI, Knauer KW, Rapp SW et al: Use of human recombinant erythropoietin and prednisone for treatment of myelodysplastic syndrome with erythroid predominance in a dog. J Am Vet Med Assoc 213:999, 1998 Breuer W, Darbes J, Hermanns W et al: Idiopathic myelofibrosis in a cat and in three dogs. Comp Haematol Int 9:17, 1999a Breuer W, Hermanns W, Thiele J: Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloproliferative disorder (CMPD) in cats. J Comp Pathol 121:203, 1999b Brown DE, Thrall MA, Getzy DM et al: Cytology of canine malignant histiocytosis. Vet Clin Pathol 23:118, 1994 Couto CG, Kallet AJ: Preleukemic syndrome in a dog. J Am Vet Med Assoc 184:1389, 1984 Dean GA, Groshek PM, Jain NC et al: Immunophenotypic analysis of feline haemolymphatic neoplasia using flow cytometry. Comp Haematol Internatl 5:84, 1995 Degen MA, Feldman BF, Turrel JM et al: Thrombocytosis associated with a myeloproliferative disorder in a dog. J Am Vet Med Assoc 194:1457, 1989 Dungworth DL, Goldman M, Switzer JW et al: Development of a myeloproliferative disorder in beagles continuously exposed to 90Sr. Blood 34:610, 1969 Dunn JK, Heath MF, Jefferies AR et al: Diagnostic and hematologic features of probable essential thrombocythemia in two dogs. Vet Clin Pathol 28:131, 1999 Evans RJ, Jones DRE, Gruffydd-Jones TJ: Essential thrombocythaemia in the dog and cat: a report of four cases. J Small Anim Pract 23:457, 1982 Favier RP, van Leeuwen M, Teske E: Essential thrombocythemia in two dogs. Tijdschr Diergeneeskd 129:360, 2004 Fernandes PJ, Modiano JF, Wojcieszyn J et al: Use of the Cell-Dyn 3500 to predict leukemic cell lineage in peripheral blood of dogs and cats. Vet Clin Pathol 31:167, 2002 Fine DM, Tvedten HW: Chronic granulocytic leukemia in a dog. J Am Vet Med Assoc 214:1809, 1999 Goldman EE, Graham JC: Clinical diagnosis and management of acute nonlymphoid leukemias and chronic myeloproliferative disorders. p. 706. In Feldman BF, Zinkl JG, Jain NC (eds): Schalm’s Veterinary Hematology. 5th Ed. Lippincott Williams & Wilkins, Philadelphia, 2000 Grindem CB: Blood cell markers. Vet Clin North Am Small Anim Pract 26:1043, 1996 Grindem CB, Buoen LC: Cytogenetic analysis of leukaemic cells in the dog. A report of 10 cases and a review of the literature. J Comp Pathol 96:623, 1986 Grindem CB, Buoen LC: Cytogenetic analysis in nine leukaemic cats. J Comp Pathol 10:21, 1989 Hamilton TA: The leukemias. p. 697. In Morrison WB (ed): Cancer in Dogs and Cats: Medical and Surgical Management. 2nd Ed. Teton NewMedia, Jackson, Wyo, 2002 Hammer AS, Couto CG, Getzy D: Essential thrombocythemia in a cat. J Vet Intern Med 4:87, 1990

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Harris NL, Jaffe ES, Diebold J et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 17:3835, 1999 Hisasue M, Nishigaki K, Katae H et al: Clonality analysis of various hematopoietic disorders in cats naturally infected with feline leukemia virus. J Vet Med Sci 62:1059, 2000 Hisasue M, Okayama H, Okayama T et al: Hematologic abnormalities and outcome of 16 cats with myelodysplastic syndromes. J Vet Intern Med 15:471, 2001 Huibregtse BA, Turner JL: Hypereosinophilic syndrome and eosinophilic leukemia: a comparison of 22 hypereosinophilic cats. J Am Anim Hosp Assoc 30:591, 1994 Jain NC: The leukemias. p. 319. In Essentials of Veterinary Hematology. Lea & Febiger, Philadelphia, 1993 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 Ledieu D, Palazzi X, Marchal T et al: Acute megakaryoblastic leukemia with erythrophagocytosis and thrombosis in a dog. Vet Clin Pathol 34: 52, 2005 Leifer CE, Matus RE, Patnaik AK et al: Chronic myelogenous leukemia in the dog. J Am Vet Med Assoc 183:686, 1983 Löwenberg B, Downing JR, Burnett A: Acute myeloid leukemia. N Engl J Med 341:1051, 1999 McManus PM: Classification of myeloid neoplasms: a comparative review. Vet Clin Pathol 34:189, 2005 McManus PM, Hess RS: Myelodysplastic changes in a dog with subsequent acute myeloid leukemia. Vet Clin Pathol 27:112, 1998 Mears EA, Raskin RE, Legendre AM: Basophilic leukemia in a dog. J Vet Intern Med 11:92, 1997 Miyamoto T, Horie T, Shimada T et al: Long-term case study of myelodysplastic syndrome in a dog. J Am Anim Hosp Assoc 35:475, 1999 Modiano JF, Smith R, Wojcieszyn J et al: The use of cytochemistry, immunophenotyping, flow cytometry, and in vitro differentiation to determine the ontogeny of a canine monoblastic leukemia. Vet Clin Pathol 27:40, 1998 Murphy S, Iland H, Rosenthal D et al: Essential thrombocythemia: an interim report from the Polycythemia Vera Study Group. Semin Hematol 23:177, 1986 Nagashima N, Kano R, Hirai A et al: Acute monocytic leukemia in a cat. Vet Rec 17:347, 2005 Ogilvie GK, Moore AS: Bone marrow neoplasia (myeloproliferative disease). p. 260. In Managing the Veterinary Cancer Patient: A Practical Manual. Veterinary Learning Systems, Trenton, NJ, 1995 Padgett GA, Madewell BR, Keller ET et al: Inheritance of histiocytosis in Bernese mountain dogs. J Small Anim Pract 36:93, 1995 Peterson ME, Randolph JF: Diagnosis of canine primary polycythemia and management with hydroxyurea. J Am Vet Med Assoc 180:415, 1982 Pucheu-Haston CM, Camus A, Taboada J et al: Megakaryoblastic leukemia in a dog. J Am Vet Med Assoc 207:194, 1995 Raskin RE: Myelopoiesis and myeloproliferative disorders. Vet Clin North Am Small Anim Pract 26:1023, 1996 Raskin RE, Krehbiel JD: Myelodysplastic changes in a cat with myelomonocytic leukemia. J Am Vet Med Assoc 187:171, 1985 Raskin RE, Valenciano A: Cytochemical tests for diagnosis of leukemia. p. 755. In Feldman BF, Zinkl JG, Jain NC (eds): Schalm’s Veterinary Hematology. 5th Ed. Lippincott Williams & Wilkins, Philadelphia, 2000 Reimann N, Bartnizke S, Bullerdiek J et al: Trisomy 1 in a canine acute leukemia indicating the pathogenetic importance of polysomy 1 in leukemias of dogs. Cancer Genet Cytogenet 101:49, 1998

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9 | Hemolymphatic System

Seed TM: Hematopoietic cell crisis: an early stage of evolving myeloid leukemia following radiation exposure. J Radiat Res (Tokyo) 32(Suppl 2):118, 1991 Simpson JW, Else RW, Honeyman P: Successful treatment of suspected essential thrombocythaemia in the dog. J Small Anim Pract 31:345, 1990 Tarrant JM, Stokol T, Blue JT et al: Diagnosis of chronic myelogenous leukemia in a dog using morphologic, cytochemical, and flow cytometric techniques. Vet Clin Pathol 30:19, 2001 Valli VE, Jacobs RM, Parodi AL et al: Histological Classification of Hematopoietic Tumors of Domestic Animals. Armed Forces Institute of Pathology, Washington, DC, 2002 Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292, 2002 Vernau W, Moore PF: An immunophenotypic study of canine leukemias and preliminary assessment of clonality by polymerase chain reaction. Vet Immunol Immunopathol 69:145, 1999 Villiers EJ, Dunn JK: Clinicopathological features of seven cases of canine myelofibrosis and the possible relationship between the histological findings and prognosis. Vet Rec 145:222, 1999 Visonneau S, Cesano A, Tran T et al: Successful treatment of canine malignant histiocytosis with the human major histocompatibility

complex nonrestricted cytotoxic T-cell line TALL-104. Clin Cancer Res 3:1789, 1997 Walton RM, Brown DE, Burkhard MJ et al: Malignant histiocytosis in a domestic cat: cytomorphologic and immunohistochemical features. Vet Clin Pathol 26:56, 1997 Watson ADJ, Moore AS, Helfand SC: Primary erythrocytosis in the cat: treatment with hydroxyurea. J Small Anim Pract 35:320, 1994 Weiss DJ: Evaluation of proliferative disorders in canine bone marrow by use of flow cytometric scatter plots and monoclonal antibodies. Vet Pathol 38:512, 2001 Weiss DJ: Recognition and classification of dysmyelopoiesis in the dog: a review. J Vet Intern Med 19:147, 2005 Weiss DJ, Aird B: Cytologic evaluation of primary and secondary myelodysplastic syndromes in the dog. Vet Clin Pathol 30:67, 2001 Weiss DJ, Smith SA: Primary myelodysplastic syndromes of dogs: a report of 12 cases. J Vet Intern Med 14:491, 2000 Weiss DJ, Smith SA: A retrospective study of 19 cases of canine myelofibrosis. J Vet Intern Med 16:174, 2002 Young KM, MacEwen EG: Canine myeloproliferative disorders. p. 495. In Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology. 2nd Ed. WB Saunders, Philadelphia, 1996